Original Article
Virus-like nanoparticle and DNA vaccination confers protection against respiratory syncytial virus by modulating innate and adaptive immune cells

https://doi.org/10.1016/j.nano.2014.07.013Get rights and content

Abstract

Respiratory syncytial virus (RSV) is an important human pathogen. Expression of virus structural proteins produces self-assembled virus-like nanoparticles (VLP). We investigated immune phenotypes after RSV challenge of immunized mice with VLP containing RSV F and G glycoproteins mixed with F-DNA (FdFG VLP). In contrast to formalin-inactivated RSV (FI-RSV) causing vaccination-associated eosinophilia, FdFG VLP immunization induced low bronchoalveolar cellularity, higher ratios of CD11c+ versus CD11b+ phenotypic cells and CD8+ T versus CD4+ T cells secreting interferon (IFN)-γ, T helper type-1 immune responses, and no sign of eosinophilia upon RSV challenge. Furthermore, RSV neutralizing activity, lung viral clearance, and histology results suggest that FdFG VLP can be comparable to live RSV in conferring protection against RSV and in preventing RSV disease. This study provides evidence that a combination of recombinant RSV VLP and plasmid DNA may have a potential anti-RSV prophylactic vaccine inducing balanced innate and adaptive immune responses.

From the Clinical Editor

This study demonstrates that a combination of recombinant RSV virus-like nanoparticles and plasmid DNA may be utilized as a prophylactic vaccine against RSV, inducing balanced innate and adaptive immune responses.

Graphical abstract

Immunization of mice with a mixed vaccine (FdFG VLP) of virus-like nanoparticles (VLPs) containing respiratory syncytial virus (RSV) F and G glycoproteins and plasmid DNA encoding RSV F induced IgG2a antibodies dominantly specific for RSV F. After RSV challenge, FdFG VLP immunized mice controlled lung viral loads as well as showed higher levels of CD8+ T cells producing interferon-gamma and did not cause eosinophilia and pulmonary inflammatory disease compared to formalin-inactivated RSV immunized mice.

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Section snippets

Preparation of RSV VLPs, RSV F encoding DNA, and FI-RSV

Nanoparticle VLP consisting of an influenza virus matrix (M1) protein core and RSV glycoproteins F (RSV F VLP) or G (RSV G VLP) on the surface were produced using the insect cell expression system and characterized as described.16 Briefly, SF9 insect cells were infected with recombinant baculoviruses expressing M1 and RSV F or RSV G proteins, and RSV VLP nanoparticles released into cell culture media were purified by ultracentrifugation.16 The plasmid DNA encoding RSV F protein (RSV F DNA) was

A combined VLP and DNA vaccine induces high IgG2a/IgG1 antibody ratios

Both F VLP and G VLP were shown to raise similar RSV neutralizing titers and control lung viral loads.16 In addition, antibody responses specific for RSV G central domains were demonstrated to contribute to conferring protection and ameliorating RSV disease.22 We found that FdFG VLP was more effective in inducing higher levels of IgG2a antibodies (Th1 type) whereas F DNA alone was not highly immunogenic (Supplementary Figure S1). Therefore, to further evaluate the protective immune responses

Discussion

Protective immune correlates are not well understood because there is no licensed RSV vaccine. In particular, cellular phenotypes contributing to protection and disease remain largely unknown after RSV vaccination. Results in this study provide evidence that FdFG VLP could confer protection against RSV by preventing pulmonary eosinophilia and modulating cellular phenotypes as well as cellularity of infiltrates and IFN-γ secreting cells in addition to inducing Th1 type antibodies and cytokines.

Acknowledgment

The authors thank T. Kang for editing the manuscript.

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  • Cited by (0)

    Funding information: This work was supported by National Institutes of Health/NIAID grants AI105170 (S.M.K.), AI093772 (S.M.K.), 1R01AI087798 (MLM), 1U19AI095227 (MLM), and NRF 2014R12014R1A2A2AA01004899 (FSQ).

    The histology core facility in the Center for Inflammation, Immunity, & Infection was supported by Georgia Research Alliance. The following reagent was obtained through the NIH Biodefense and Emerging Infections Research Resources Repository, NIAID, NIH: Respiratory Syncytial Virus A2 F soluble protein, NR-28908.

    All authors declare no conflicts of interest.

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