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Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers

Nature Biomedical Engineering (2024)Cite this article

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Abstract

Messenger RNA vaccines lack specificity for dendritic cells (DCs)—the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid–nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

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Fig. 1: Design and characterization of a VLP-based SARS-CoV-2 mRNA vaccine.
Fig. 2: VLP–S-mut mRNA induced robust and durable spike-specific antibody responses.
Fig. 3: DVLP–S-mut mRNA vaccine enhanced spike-specific immune response.
Fig. 4: DVLP–S-mut mRNA improved spike-specific humoral and T-cell responses compared with LNP–mRNA.
Fig. 5: In vivo characterization of the biodistribution and DC-targeting capability of DVLPs.
Fig. 6: The DVLP–S-mut mRNA vaccine efficiently protected hACE2-transgenic mice from SARS-CoV-2 challenge.
Fig. 7: The DVLP-mediated delivery of gB1 and gD1 mRNA efficiently protected mice from HSV-1 infection.

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Data availability

Source data for the figures are available from figshare51 at https://doi.org/10.6084/m9.figshare.24516694. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

References

  1. Roth, G. A. et al. Designing spatial and temporal control of vaccine responses. Nat. Rev. Mater. 7, 174–195 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Colby, D. J. et al. Safety and immunogenicity of Ad26 and MVA vaccines in acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption. Nat. Med. 26, 498–501 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Ng’uni, T., Chasara, C. & Ndhlovu, Z. M. Major scientific hurdles in HIV vaccine development: historical perspective and future directions. Front. Immunol. 11, 590780 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bernstein, D. I. et al. The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model. npj Vaccines 5, 104 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Awasthi, S. et al. Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. Sci. Immunol. 4, eaaw7083 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang, W. et al. Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B. Nat. Nanotechnol. 15, 406–416 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Roden, R. B. S. & Stern, P. L. Opportunities and challenges for human papillomavirus vaccination in cancer. Nat. Rev. Cancer 18, 240–254 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Widge, A. T. et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N. Engl. J. Med. 384, 80–82 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Thomas, S. J. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine through 6 months. N. Engl. J. Med. 385, 1761–1773 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Y. et al. mRNA vaccine: a potential therapeutic strategy. Mol. Cancer 20, 33 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lindsay, K. E. et al. Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging. Nat. Biomed. Eng. 3, 371–380 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Chen, J. et al. Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response. Proc. Natl Acad. Sci. USA 119, e2207841119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tenforde, M. W. et al. Effectiveness of severe acute respiratory syndrome coronavirus 2 messenger RNA vaccines for preventing coronavirus disease 2019 hospitalizations in the United States. Clin. Infect. Dis. 74, 1515–1524 (2022).

    Article  CAS  PubMed  Google Scholar 

  18. Eisenbarth, S. C. Dendritic cell subsets in T cell programming: location dictates function. Nat. Rev. Immunol. 19, 89–103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lanzavecchia, A. & Sallusto, F. Regulation of T cell immunity by dendritic cells. Cell 106, 263–266 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Heath, W. R., Kato, Y., Steiner, T. M. & Caminschi, I. Antigen presentation by dendritic cells for B cell activation. Curr. Opin. Immunol. 58, 44–52 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Wykes, M., Pombo, A., Jenkins, C. & MacPherson, G. G. Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response. J. Immunol. 161, 1313–1319 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Igyarto, B. Z., Jacobsen, S. & Ndeupen, S. Future considerations for the mRNA-lipid nanoparticle vaccine platform. Curr. Opin. Virol. 48, 65–72 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Blumenthal, K. G. et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N. Engl. J. Med. 384, 1273–1277 (2021).

    Article  PubMed  Google Scholar 

  24. Yu, Y. et al. Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients. Signal Transduct. Target. Ther. 6, 346 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Svajger, U., Anderluh, M., Jeras, M. & Obermajer, N. C-type lectin DC-SIGN: an adhesion, signalling and antigen-uptake molecule that guides dendritic cells in immunity. Cell. Signal. 22, 1397–1405 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang, L. et al. Engineered lentivector targeting of dendritic cells for in vivo immunization. Nat. Biotechnol. 26, 326–334 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, eabb2507 (2020).

    Article  Google Scholar 

  28. Yin, D. et al. Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice. Nat. Biotechnol. 39, 567–577 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ling, S. et al. Lentiviral delivery of co-packaged Cas9 mRNA and a Vegfa-targeting guide RNA prevents wet age-related macular degeneration in mice. Nat. Biomed. Eng. 5, 144–156 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Segel, M. et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science 373, 882–889 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Banskota, S. et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell 185, 250–265.e16 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu, B., Tai, A. & Wang, P. Immunization delivered by lentiviral vectors for cancer and infectious diseases. Immunol. Rev. 239, 45–61 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chang, D. & Zaia, J. Why glycosylation matters in building a better flu vaccine. Mol. Cell. Proteomics 18, 2348–2358 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Watanabe, Y., Allen, J. D., Wrapp, D., McLellan, J. S. & Crispin, M. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 369, eabb9983 (2020).

    Article  Google Scholar 

  35. Neerukonda, S. N. et al. Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2. PLoS ONE 16, e0248348 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wienert, B., Shin, J., Zelin, E., Pestal, K. & Corn, J. E. In vitro-transcribed guide RNAs trigger an innate immune response via the RIG-I pathway. PLoS Biol. 16, e2005840 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Mu, X., Greenwald, E., Ahmad, S. & Hur, S. An origin of the immunogenicity of in vitro transcribed RNA. Nucleic Acids Res. 46, 5239–5249 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ying, T. et al. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J. Virol. 88, 7796–7805 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ma, M. L. et al. Systematic profiling of SARS-CoV-2-specific IgG responses elicited by an inactivated virus vaccine identifies peptides and proteins for predicting vaccination efficacy. Cell Discov. 7, 67 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jiang, H. W. et al. SARS-CoV-2 proteome microarray for global profiling of COVID-19 specific IgG and IgM responses. Nat. Commun. 11, 3581 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li, Y. et al. Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients. Cell Rep. 34, 108915 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lu, J. et al. A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice. Cell Res. 30, 936–939 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bao, L. et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 583, 830–833 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Kastenmuller, W., Kastenmuller, K., Kurts, C. & Seder, R. A. Dendritic cell-targeted vaccines—hope or hype? Nat. Rev. Immunol. 14, 705–711 (2014).

    Article  PubMed  Google Scholar 

  46. Ku, M.-W., Charneau, P. & Majlessi, L. Use of lentiviral vectors in vaccination. Expert Rev. Vaccines 20, 1571–1586 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Pollack, S. M. et al. First-in-human treatment with a dendritic cell-targeting lentiviral vector-expressing NY-ESO-1, LV305, induces deep, durable response in refractory metastatic synovial sarcoma patient. J. Immunother. 40, 302–306 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ku, M. W. et al. Lentiviral vector induces high-quality memory T cells via dendritic cells transduction. Commun. Biol. 4, 713 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ku, M. W. et al. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models. Cell Host Microbe 29, 236–249.e6 (2021).

    Article  CAS  PubMed  Google Scholar 

  50. Norton, T. D. & Miller, E. A. Recent advances in lentiviral vaccines for HIV-1 infection. Front. Immunol. 7, 243 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Zhong, Y. SD_FIG1-7.xlsx.xlsx. figshare https://doi.org/10.6084/m9.figshare.24516694 (2023).

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Acknowledgements

Y.C. is supported by the National Key R&D Program of China (2022YFC3400205), the National Natural Science Foundation of China (31971364) and Shanghai Jiao Tong University Scientific and Technological Innovation Funds (AF4150049). J.H. is supported by the National Natural Science Foundation of China (81970766 and 82171102) and the Shanghai Innovation Development Program (2020-RGZN-02033). T.Y. is supported by the National Key R&D Program of China (2019YFA0904400) and the National Natural Science Foundation of China (81822027 and 81630090). S.T. is supported by the National Natural Science Foundation of China (31970130) and the National Key R&D Program of China (2020YFE0202200).

Author information

Author notes

  1. These authors contributed equally: Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Xiaoyuan Wang.

Authors and Affiliations

  1. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China

    Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Zhuofan Jiang, Jie Wang, Yao Dai, Qijing Huang, Junsong Chen, Ziying Li, Yang Li, Zhijue Xu, Hewei Jiang, Yan Zhang, Lintai Da, Ze-guang Han, Sheng-ce Tao, Ruijiao Dong & Yujia Cai

  2. BDGENE Therapeutics, Shanghai, China

    Sikai Ling & Xiaoyuan Wang

  3. MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Xiaolong Tian & Tianlei Ying

  4. MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China

    Xingbo Wang

  5. Department of Ophthalmology and Vision Science, Shanghai Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China

    Yuqing Wu, Jianjiang Xu & Jiaxu Hong

  6. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China

    Yi Shi

  7. National Beijing Center for Drug Safety Evaluation and Research, State Key Laboratory of Medical Countermeasures and Toxicology, Institute of Pharmacology and Toxicology, Academy of Military Sciences, Beijing, China

    Quanjun Wang

  8. CAS Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

    Wei Hong, Heng Xue & Hang Yang

  9. University of Chinese Academy of Sciences, Beijing, China

    Wei Hong, Heng Xue & Hang Yang

  10. Hubei Jiangxia Laboratory, Wuhan, China

    Hang Yang

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  1. Di Yin
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Contributions

Y.C. conceived the study and designed the experiments; D.Y., Y. Zhong, S. Ling, S. Lu, Xiaoyuan Wang, Z.J., J.W., Y.D., X.T., Q.H., Xingbo Wang, J.C., Z.L., Y.L., Z.X., H.J., Y.W., Y.S., Q.W., J.X., W.H., H.X., H.Y., Y. Zhang, L.D., Z.H., S.T., R.D., T.Y. and J.H. performed the experiments or provided essential experimental resources; all the authors analysed the data; Y. Zhong, D.Y., S. Ling, and Y.C. wrote the manuscript with help from all the authors.

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Correspondence to Jiaxu Hong or Yujia Cai.

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Y.C. is a co-founder and advisor of BDGENE Therapeutics. The other authors declare no competing interests.

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Yin, D., Zhong, Y., Ling, S. et al. Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01208-4

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