A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2
Source abstract
Abstract
Abstract The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8 + T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.
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Research context
OpenAlex topics: Respiratory viral infections research · Immunotherapy and Immune Responses · Immune Cell Function and Interaction
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (60)
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1. Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21, 83–100 (2021).10.1038/s41577-020-00479-7 ↗
2. Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020).10.1038/s41586-020-2798-3 ↗
3. Innis, B. L. et al. Meeting report: Convening on the influenza human viral challenge model for universal influenza vaccines, part 1: value; challenge virus selection; regulatory, industry and ethical considerations; increasing standardization, access and capacity. Vaccine 37, 4823–4829 (2019).10.1016/j.vaccine.2019.06.080 ↗
4. Mlcochova, P. et al. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature 599, 114–119 (2021).10.1038/s41586-021-03944-y ↗
5. Planas, D. et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 596, 276–280 (2021).10.1038/s41586-021-03777-9 ↗
6. Abdool Karim, S. S. & de Oliveira, T. New SARS-CoV-2 variants—clinical, public health, and vaccine implications. N. Engl. J. Med. 384, 1866–1868 (2021).10.1056/NEJMc2100362 ↗
7. Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl Acad. Sci. USA 111, 13133–13138 (2014).10.1073/pnas.1414070111 ↗
8. Tan, H. X. et al. Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. J. Clin. Invest. 129, 850–862 (2019).10.1172/JCI123366 ↗
9. Lopez-Sagaseta, J., Malito, E., Rappuoli, R. & Bottomley, M. J. Self-assembling protein nanoparticles in the design of vaccines. Comput. Struct. Biotechnol. J. 14, 58–68 (2016).10.1016/j.csbj.2015.11.001 ↗
10. Haynes, J. R. Influenza virus-like particle vaccines. Expert Rev. Vaccines 8, 435–445 (2009).10.1586/erv.09.8 ↗
11. Schwartzman, L. M. et al. An intranasal virus-like particle vaccine broadly protects mice from multiple subtypes of influenza A virus. mBio 6, e01044 (2015).10.1128/mBio.01044-15 ↗
12. Boyoglu-Barnum, S. et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 592, 623–628 (2021).10.1038/s41586-021-03365-x ↗
13. Yassine, H. M. et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21, 1065–1070 (2015).10.1038/nm.3927 ↗
14. Impagliazzo, A. et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 349, 1301–1306 (2015).10.1126/science.aac7263 ↗
15. Steel, J. et al. Influenza virus vaccine based on the conserved hemagglutinin stalk domain. mBio 1, e00018–10 (2010).10.1128/mBio.00018-10 ↗
16. Mallajosyula, V. V. et al. Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection. Proc. Natl Acad. Sci. USA 111, E2514–E2523 (2014).10.1073/pnas.1402766111 ↗
17. Reed, S. G., Orr, M. T. & Fox, C. B. Key roles of adjuvants in modern vaccines. Nat. Med. 19, 1597–1608 (2013).10.1038/nm.3409 ↗
18. Pulendran, B., Arunachalam, P. S. & O'Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20, 454–475 (2021).10.1038/s41573-021-00163-y ↗
19. Khurana, S. et al. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci. Transl. Med. 3, 85ra48 (2011).10.1126/scitranslmed.3002336 ↗
20. He, P., Zou, Y. & Hu, Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum. Vaccin. Immunother. 11, 477–488 (2015).10.1080/21645515.2014.1004026 ↗
21. Maisonneuve, C., Bertholet, S., Philpott, D. J. & De Gregorio, E. Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc. Natl Acad. Sci. USA 111, 12294–12299 (2014).10.1073/pnas.1400478111 ↗
22. Wille-Reece, U. et al. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc. Natl. Acad. Sci. USA 102, 15190–15194 (2005).10.1073/pnas.0507484102 ↗
23. Wille-Reece, U. et al. Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J. Exp. Med. 203, 1249–1258 (2006).10.1084/jem.20052433 ↗
24. Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011).10.1038/nature09737 ↗
25. Kasturi, S. P. et al. Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques. J. Virol. 91, e01844–16 (2017).10.1128/JVI.01844-16 ↗
26. Om, K. et al. Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge. PLoS Pathog. 16, e1008764 (2020).10.1371/journal.ppat.1008764 ↗
27. Arunachalam, P. S. et al. T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers. Nat. Med. 26, 932–940 (2020).10.1038/s41591-020-0858-8 ↗
28. Vasilakos, J. P. & Tomai, M. A. The use of Toll-like receptor 7/8 agonists as vaccine adjuvants. Expert Rev. Vaccines 12, 809–819 (2013).10.1586/14760584.2013.811208 ↗
29. Kasturi, S. P. et al. 3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates. Sci. Immunol. 5, eabb1025 (2020).10.1126/sciimmunol.abb1025 ↗
30. Petitdemange, C. et al. Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques. JCI Insight 4, e126047 (2019).10.1172/jci.insight.126047 ↗
31. Pino, M. et al. A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates. Sci. Immunol. 6, eabh3634 (2021).10.1126/sciimmunol.abh3634 ↗
32. Fox, C. B. et al. Adsorption of a synthetic TLR7/8 ligand to aluminum oxyhydroxide for enhanced vaccine adjuvant activity: a formulation approach. J. Control. Release 244, 98–107 (2016).10.1016/j.jconrel.2016.11.011 ↗
33. Arunachalam, P. S. et al. Adjuvanting a subunit COVID-19 vaccine to induce protective immunity. Nature 594, 253–258 (2021).10.1038/s41586-021-03530-2 ↗
34. Gonzalez-Lopez, A. et al. Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): a phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine. Clin. Immunol. 209, 108275 (2019).10.1016/j.clim.2019.108275 ↗
35. Yin, Q. et al. Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis. Proc. Natl Acad. Sci. USA 113, E4601–E4609 (2016).10.1073/pnas.1603316113 ↗
36. Yin, Q. et al. Drug-initiated ring-opening polymerization of O-carboxyanhydrides for the preparation of anticancer drug-poly(O-carboxyanhydride) nanoconjugates. Biomacromolecules 14, 920–929 (2013).10.1021/bm301999c ↗
37. Yin, Q., Yin, L., Wang, H. & Cheng, J. Synthesis and biomedical applications of functional poly(α-hydroxy acids) via ring-opening polymerization of O-carboxyanhydrides. Acc. Chem. Res. 48, 1777–1787 (2015).10.1021/ar500455z ↗
38. Shlomchik, M. J., Luo, W. & Weisel, F. Linking signaling and selection in the germinal center. Immunol. Rev. 288, 49–63 (2019).10.1111/imr.12744 ↗
39. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).10.1038/nm.2426 ↗
40. Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).10.1038/s41591-020-01145-0 ↗
41. Walls, A. C. et al. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Cell 183, 1367–1382 e1317 (2020).10.1016/j.cell.2020.10.043 ↗
42. Deguine, J. & Barton, G. M. MyD88: a central player in innate immune signaling. F1000Prime Rep. 6, 97 (2014).10.12703/P6-97 ↗
43. Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).10.1038/nmat3775 ↗
44. Luo, W. & Yin, Q. B cell response to vaccination. Immunol. Invest. 50, 780–801 (2021).10.1080/08820139.2021.1903033 ↗
45. Victora, G. D. & Wilson, P. C. Germinal center selection and the antibody response to influenza. Cell 163, 545–548 (2015).10.1016/j.cell.2015.10.004 ↗
46. Havenar-Daughton, C., Lee, J. H. & Crotty, S. Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem. Immunol. Rev. 275, 49–61 (2017).10.1111/imr.12512 ↗
47. Mesin, L., Ersching, J. & Victora, G. D. Germinal center B cell dynamics. Immunity 45, 471–482 (2016).10.1016/j.immuni.2016.09.001 ↗
48. Abbott, R. K. & Crotty, S. Factors in B cell competition and immunodominance. Immunol. Rev. 296, 120–131 (2020).10.1111/imr.12861 ↗
49. Akram, A. & Inman, R. D. Immunodominance: a pivotal principle in host response to viral infections. Clin. Immunol. 143, 99–115 (2012).10.1016/j.clim.2012.01.015 ↗
50. Abbott, R. K. et al. Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity 48, 133–146 e136 (2018).10.1016/j.immuni.2017.11.023 ↗
51. Brandes, M., Klauschen, F., Kuchen, S. & Germain, R. N. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell 154, 197–212 (2013).10.1016/j.cell.2013.06.013 ↗
52. Sinclair, C. et al. mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation. Science 357, 1014–1021 (2017).10.1126/science.aaj2155 ↗
53. Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 e1821 (2019).10.1016/j.cell.2019.05.031 ↗
54. Mou, T., Deng, W., Gu, F., Pawitan, Y. & Vu, T. N. Reproducibility of methods to detect differentially expressed genes from single-cell RNA sequencing. Front. Genet. 10, 1331 (2019).10.3389/fgene.2019.01331 ↗
55. Huang da, W., Sherman, B. T. & Lempicki, R. A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).10.1093/nar/gkn923 ↗
56. Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).10.1038/nprot.2008.211 ↗
57. Dermadi, D. et al. Exploration of cell development pathways through high-dimensional single cell analysis in trajectory space. iScience 23, 100842 (2020).10.1016/j.isci.2020.100842 ↗
58. Chiu, C. H., Wang, Y. T., Walther, B. A. & Chao, A. An improved nonparametric lower bound of species richness via a modified Good–Turing frequency formula. Biometrics 70, 671–682 (2014).10.1111/biom.12200 ↗
59. Spassova, I. et al. Predominance of central memory T cells with high T-cell receptor repertoire diversity is associated with response to PD-1/PD-L1 inhibition in merkel cell carcinoma. Clin. Cancer Res. 26, 2257–2267 (2020).10.1158/1078-0432.CCR-19-2244 ↗
60. Carey, A. J. et al. Public clonotypes and convergent recombination characterize the naive CD8+ T-cell receptor repertoire of extremely preterm neonates. Front. Immunol. 8, 1859 (2017).10.3389/fimmu.2017.01859 ↗