Virus-like particles coexpressing the PreF and Gt antigens of respiratory syncytial virus confer protection in mice
Abstract
Aims: The purpose of this study was to assess the protective efficacy of virus-like particles (VLPs) co-expressing the pre-fusogenic (PreF) and G protein with tandem repeats (Gt) antigens of respiratory syncytial virus (RSV) in mice. Materials & methods: VLP constructs expressing PreF, Gt or both were used to immunize mice, and the protective efficacies were evaluated using antibody responses, neutralizing antibody titers, T-cell responses, histopathological assessment and plaque assay. Results: PreF+Gt VLP immunization elicited strong RSV-specific antibody responses and pulmonary T-cell responses that contributed to lessening virus titer and inflammation. Conclusion: Our findings suggest that coexpressing PreF and Gt antigens elicits better protection than either one alone. This combinatorial approach could assist in future RSV vaccine development.
References
- 1. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 390(10098), 946–958 (2017).
- 2. . Virus-like particles as a highly efficient vaccine platform: diversity of targets and production systems and advances in clinical development. Vaccine 31(1), 58–83 (2012).
- 3. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect. Dis. 18(10), e295–e311 (2018).
- 4. . Fail-fast in respiratory syncytial virus vaccine development. Am. J. Respir. Crit. Care Med. 200(4), 410–412 (2019).
- 5. . Profile of respiratory syncytial virus prefusogenic fusion protein nanoparticle vaccine. Expert Rev. Vaccines 20(4), 351–364 (2021).
- 6. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342(6158), 592–598 (2013).
- 7. . Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus. Sci. Rep. 6, 34108 (2016).
- 8. Immunogenicity and protective efficacy of adenoviral and subunit RSV vaccines based on stabilized prefusion F protein in pre-clinical models. Vaccine 40(6), 934–944 (2021).
- 9. Prevention of respiratory syncytial virus infection in healthy adults by a single immunization of Ad26.RSV.preF in a human challenge study. J. Infect. Dis. 226(3), 396–406 (2022).
- 10. Safety and immunogenicity of the Ad26.RSV.preF investigational vaccine coadministered with an influenza vaccine in older adults. J. Infect. Dis. 223(4), 699–708 (2021).
- 11. Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: structure, antigenic profile, immunogenicity, and protection. Vaccine 37(41), 6112–6124 (2019).
- 12. Maternal immunization with RSV fusion glycoprotein vaccine and substantial protection of neonatal baboons against respiratory syncytial virus pulmonary challenge. Vaccine 38(5), 1258–1270 (2020).
- 13. Antigenicity and immunogenicity of unique prefusion-mimic F proteins presented on enveloped virus-like particles. Vaccine 37(44), 6656–6664 (2019).
- 14. A respiratory syncytial virus (RSV) F protein nanoparticle vaccine focuses antibody responses to a conserved neutralization domain. Sci. Immunol. 5(47), eaba6466 (2020).
- 15. Flexible RSV prefusogenic fusion glycoprotein exposes multiple neutralizing epitopes that may collectively contribute to protective immunity. Vaccines (Basel.) 8(4), 607 (2020).
- 16. . Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination. J. Med. Virol. 64(3), 290–298 (2001).
- 17. . Protection induced by virus-like particle vaccine containing tandem repeat gene of respiratory syncytial virus G protein. PLOS ONE 13(1), e0191277 (2018).
- 18. Viruslike particle vaccine induces protection against respiratory syncytial virus infection in mice. J. Infect. Dis. 204(7), 987–995 (2011).
- 19. . A rapid, simple, and accurate plaque assay for human respiratory syncytial virus (HRSV). J. Immunol. Methods 446, 15–20 (2017).
- 20. Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs. PLOS ONE 14(6), e0216871 (2019).
- 21. Additive protection induced by mixed virus-like particles presenting respiratory syncytial virus fusion or attachment glycoproteins. Antiviral Res. 111, 129–135 (2014).
- 22. Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease. Virology 494, 215–224 (2016).
- 23. . The importance of RSV F protein conformation in VLPs in stimulation of neutralizing antibody titers in mice previously infected with RSV. Hum. Vaccin. Immunother. 13(12), 2814–2823 (2017).
- 24. . Influenza virus matrix protein is the major driving force in virus budding. J. Virol. 74(24), 11538–11547 (2000).
- 25. . Assembly and entry of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2): evaluation using virus-like particles. Cells 10(4), 853 (2021).
- 26. . Passive IgA monoclonal antibody is no more effective than IgG at protecting mice from mucosal challenge with respiratory syncytial virus. J. Infect. Dis. 180(4), 1324–1327 (1999).
- 27. An assessment of different DNA delivery systems for protection against respiratory syncytial virus infection in the murine model: gene-gun delivery induces IgG in the lung. Vaccine 22(19), 2438–2443 (2004).
- 28. . Nasal-associated lymphoid tissue is a site of long-term virus-specific antibody production following respiratory virus infection of mice. J. Virol. 75(11), 5416–5420 (2001).
- 29. . Nasal-associated lymphoid tissue (NALT): frequency and localization in young children. Clin. Exp. Immunol. 134(3), 503–507 (2003).
- 30. A role for immune complexes in enhanced respiratory syncytial virus disease. J. Exp. Med. 196(6), 859–865 (2002).
- 31. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 15(1), 34–41 (2009).
- 32. . Absence of vaccine-enhanced RSV disease and changes in pulmonary dendritic cells with adenovirus-based RSV vaccine. Virol. J. 8, 375 (2011).
- 33. . Clearance of persistent respiratory syncytial virus infections in immunodeficient mice following transfer of primed T cells. Immunology 62(1), 133–138 (1987).
- 34. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat. Commun. 6, 10224 (2015).
- 35. . The CD8 T cell response to respiratory virus infections. Front. Immunol. 9, 678 (2018).
- 36. . Cytokines and CD8 T cell immunity during respiratory syncytial virus infection. Cytokine 133, 154481 (2020).
- 37. . Virus clearance and immunopathology by CD8(+) T cells during infection with respiratory syncytial virus are mediated by IFN-gamma. Eur. J. Immunol. 32(8), 2117–2123 (2002).
- 38. Virus-like particle vaccines containing F or F and G proteins cofer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats. Hum. Vaccin. Immunother.. 13(5), 1031–1039 (2017).
- 39. . Nonglycosylated G-protein vaccine protects against homologous and heterologous respiratory syncytial virus (RSV) challenge, while glycosylated G enhances RSV lung pathology and cytokine levels. J. Virol. 89(16), 8193–8205 (2015).
- 40. . Humanization of lepidopteran insect-cell-produced glycoproteins. Acc. Chem. Res. 36(8), 613–620 (2003).
- 41. . Murine immune responses to virus-like particle-associated pre- and postfusion forms of the respiratory syncytial virus F protein. J. Virol. 89(13), 6835–6847 (2015).
- 42. 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. J. Virol. 89(22), 11692–11705 (2015).
- 43. Evaluation of multivalent H2 influenza pandemic vaccines in mice. Vaccine 35(10), 1455–1463 (2017).
- 44. Cellular immune correlates preventing disease against respiratory syncytial virus by vaccination with virus-like nanoparticles carrying fusion proteins. J. Biomed. Nanotechnol. 13(1), 84–98 (2017).
- 45. Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages. Int. J. Nanomed. 10, 4491–4505 (2015).
- 46. Quantitative characterization of virus-like particles by asymmetrical flow field flow fractionation, electrospray differential mobility analysis, and transmission electron microscopy. Biotechnol. Bioeng. 102(3), 845–855 (2009).
- 47. Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers. J. Nanobiotechnol. 19(1), 59 (2021).