Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines
Source abstract
Abstract
Lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) vaccineare a promising platform to prevent infectious diseases as demonstrated by the recent success of SARS-CoV-2 mRNA vaccines. To avoid immune recognition and uncontrolled inflammation, nucleoside-modified mRNA is used. However, such modification largely abrogates the innate immune responses that are critical to orchestrating robust adaptive immunity. Here we develop an LNP component-an adjuvant lipidoid-that can enhance the adjuvanticity of mRNA-LNP vaccines. Our results show that partial substitution of ionizable lipidoid with adjuvant lipidoid not only enhanced mRNA delivery, but also endowed LNPs with Toll-like receptor 7/8-agonistic activity, which significantly increased the innate immunity of the SARS-CoV-2 mRNA-LNP vaccine with good tolerability in mice. Our optimized vaccine elicits potent neutralizing antibodies against multiple SARS-CoV-2 pseudovirus variants, strong Th1-biased cellular immunity, and robust B cell and long-lived plasma cell responses. Importantly, this adjuvant lipidoid substitution strategy works successfully in a clinically relevant mRNA-LNP vaccine, demonstrating its translational potential.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: RNA Interference and Gene Delivery · Animal Virus Infections Studies · SARS-CoV-2 and COVID-19 Research
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (47)
Show source-provided references
1. Le, T. T. et al. Evolution of the COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 19, 667–668 (2020).10.1038/d41573-020-00151-8 ↗
2. Lauring, A. S. et al. Clinical severity of, and effectiveness of mRNA vaccines against, COVID-19 from Omicron, Delta, and Alpha SARS-CoV-2 variants in the United States: prospective observational study. BMJ 376, e069761 (2022).10.1136/bmj-2021-069761 ↗
3. Pardi, N. et al. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).10.1038/nrd.2017.243 ↗
4. Yang, R. et al. A core–shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct. Target Ther. 6, 213 (2021).10.1038/s41392-021-00634-z ↗
5. Brenner, S., Jacob, F. & Meselson, M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature 190, 576–581 (1961).10.1038/190576a0 ↗
6. Buschmann, M. D. et al. Nanomaterial delivery systems for mRNA vaccines. Vaccines (Basel) 9, 65 (2021).10.3390/vaccines9010065 ↗
7. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).10.1038/s41573-020-0090-8 ↗
8. Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat. Commun. 12, 7233 (2021).10.1038/s41467-021-27493-0 ↗
9. Han, X., Mitchell, M. J. & Nie, G. Nanomaterials for therapeutic RNA delivery. Matter 3, 1948–1975 (2020).10.1016/j.matt.2020.09.020 ↗
10. Kariko, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).10.1038/mt.2008.200 ↗
11. Kariko, K. et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).10.1016/j.immuni.2005.06.008 ↗
12. Oberli, M. A. et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 17, 1326–1335 (2017).10.1021/acs.nanolett.6b03329 ↗
13. Sahin, U., Kariko, K. & Tureci, O. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014).10.1038/nrd4278 ↗
14. Alameh, M. G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e7 (2021).10.1016/j.immuni.2021.11.001 ↗
15. Swaminathan, G. et al. A novel lipid nanoparticle adjuvant significantly enhances B cell and T cell responses to sub-unit vaccine antigens. Vaccine 34, 110–119 (2016).10.1016/j.vaccine.2015.10.132 ↗
16. Swaminathan, G. et al. A tetravalent sub-unit dengue vaccine formulated with ionizable cationic lipid nanoparticle induces significant immune responses in rodents and non-human primates. Sci. Rep. 6, 34215 (2016).10.1038/srep34215 ↗
17. Coffman, R. L., Sher, A. & Seder, R. A. Vaccine adjuvants: putting innate immunity to work. Immunity 33, 492–503 (2010).10.1016/j.immuni.2010.10.002 ↗
18. Dubensky, T. W. Jr. & Reed, S. G. Adjuvants for cancer vaccines. Semin. Immunol. 22, 155–161 (2010).10.1016/j.smim.2010.04.007 ↗
19. Gerster, J. F. et al. Synthesis and structure–activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production. J. Med. Chem. 48, 3481–3491 (2005).10.1021/jm049211v ↗
20. Auderset, F. et al. A TLR7/8 agonist-including DOEPC-based cationic liposome formulation mediates its adjuvanticity through the sustained recruitment of highly activated monocytes in a type I IFN-independent but NF-γB-dependent manner. Front. Immunol. 11, 580974 (2020).10.3389/fimmu.2020.580974 ↗
21. Wang, J. et al. Lipidation approaches potentiate adjuvant-pulsed immune surveillance: a design rationale for cancer nanovaccine. Front. Bioeng. Biotechnol. 8, 787 (2020).10.3389/fbioe.2020.00787 ↗
22. Islam, M. A. et al. Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice. Biomaterials 266, 120431 (2021).10.1016/j.biomaterials.2020.120431 ↗
23. Wilson, D. S. et al. Antigens reversibly conjugated to a polymeric glyco-adjuvant induce protective humoral and cellular immunity. Nat. Mater. 18, 175–185 (2019).10.1038/s41563-018-0256-5 ↗
24. Lynn, G. M. et al. In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. Nat. Biotechnol. 33, 1201–1210 (2015).10.1038/nbt.3371 ↗
25. Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).10.1073/pnas.0910603106 ↗
26. Zhang, Z. et al. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity 45, 737–748 (2016).10.1016/j.immuni.2016.09.011 ↗
27. Gentile, F. et al. Structure based modeling of small molecules binding TLR7 by atomistic level simulations. Molecules 20, 8316–8340 (2015).10.3390/molecules20058316 ↗
28. Shukla, N. M. et al. Potent adjuvanticity of a pure TLR7-agonistic imidazoquinoline dendrimer. PLoS ONE 7, e43612 (2012).10.1371/journal.pone.0043612 ↗
29. Rodell, C. B. et al. Development of adamantane-conjugated TLR7/8 agonists for supramolecular delivery and cancer immunotherapy. Theranostics 9, 8426–8436 (2019).10.7150/thno.35434 ↗
30. Billingsley, M. M. et al. Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. Nano Lett. 20, 1578–1589 (2020).10.1021/acs.nanolett.9b04246 ↗
31. Kauffman, K. J. et al. Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Lett. 15, 7300–7306 (2015).10.1021/acs.nanolett.5b02497 ↗
32. Li, B. et al. An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett. 15, 8099–8107 (2015).10.1021/acs.nanolett.5b03528 ↗
33. Riley, R. S. et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci. Adv. 7, eaba1028 (2021).10.1126/sciadv.aba1028 ↗
34. Whitehead, K. A. et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat. Commun. 5, 4277 (2014).10.1038/ncomms5277 ↗
35. Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. 124, 8657–8661 (2012).10.1002/ange.201203263 ↗
36. Laczko, D. et al. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 53, 724–732.e7 (2020).10.1016/j.immuni.2020.07.019 ↗
37. Alishetty, S. et al. Novel lipid nanoparticle provides potent SARS-CoV-2 mRNA vaccine at low dose with low local reactogenicity, high thermostability and limited systemic biodistribution. Preprint available at Research Square https://doi.org/10.21203/rs.3.rs-798453/v1 (2021).10.21203/rs.3.rs-798453/v1 ↗
38. Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217, 345–351 (2015).10.1016/j.jconrel.2015.08.007 ↗
39. Davies, N. et al. Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein. Mol. Ther. Nucleic Acids 24, 369–384 (2021).10.1016/j.omtn.2021.03.008 ↗
40. Darrah, P. A. et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat. Med. 13, 843–850 (2007).10.1038/nm1592 ↗
41. Precopio, M. L. et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 204, 1405–1416 (2007).10.1084/jem.20062363 ↗
42. Almeida, J. R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. 204, 2473–2485 (2007).10.1084/jem.20070784 ↗
43. Guerrini, G. et al. Characterization of nanoparticles-based vaccines for COVID-19. Nat. Nanotechnol. 17, 570–576 (2022).10.1038/s41565-022-01129-w ↗
44. Zuccarino-Catania, G. V. et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637 (2014).10.1038/ni.2914 ↗
45. Momany, F. A. & Rone, R. Validation of the general-purpose Quanta(R)3.2/Charmm(R) force-field. J. Comput. Chem. 13, 888–900 (1992).10.1002/jcc.540130714 ↗
46. Wu, G. et al. Detailed analysis of grid-based molecular docking: a case study of CDOCKER—a CHARMm-based MD docking algorithm. J. Comput. Chem. 24, 1549–1562 (2003).10.1002/jcc.10306 ↗
47. Frey, A., Di Canzio, J. & Zurakowski, D. A statistically defined endpoint titer determination method for immunoassays. J. Immunol. Methods 221, 35–41 (1998).10.1016/S0022-1759(98)00170-7 ↗