A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2

Yin, Qian; Luo, Wei; Mallajosyula, Vamsee; Bo, Yang; Guo, Jing; Xie, Jinghang; Sun, Meng; Verma, Rohit; Li, Chunfeng; Constantz, Christian M.; Wagar, Lisa E.; Li, Jing; Sola, Elsa; Gupta, Neha; Wang, Chunlin; Kask, Oliver; Chen, Xin; Yuan, Xue; Wu, Nicholas C.; Rao, Jianghong; Chien, Yueh-hsiu; Cheng, Jianjun; Pulendran, Bali; Davis, Mark M.

doi:10.1038/s41563-022-01464-2

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2

Journal Article · Mon Jan 30 00:00:00 EST 2023 · Nature Materials

DOI:https://doi.org/10.1038/s41563-022-01464-2· OSTI ID:1923248

Yin, Qian ^[1]; ^[2]; ^[2]; Bo, Yang ^[3]; ^[2]; ^[2]; Sun, Meng ^[2]; Verma, Rohit ^[2]; Li, Chunfeng ^[2]; Constantz, Christian M. ^[2]; ^[2]; Li, Jing ^[2]; Sola, Elsa ^[2]; Gupta, Neha ^[2]; Wang, Chunlin ^[2]; Kask, Oliver ^[2]; Chen, Xin ^[2]; Yuan, Xue ^[4]; ^[3]; ^[5] more »

Stanford University, CA (United States). School of Medicine; SLAC
Stanford University, CA (United States). School of Medicine
University of Illinois at Urbana-Champaign, IL (United States)
Indiana Univ., Indianapolis, IN (United States)
Stanford Univesity, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Stanford Univesity, CA (United States)

Sponsoring Organization:: Bill and Melinda Gates Foundation; National Institutes of Health (NIH); Soffer Fund endowment; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1923248

Journal Information:: Nature Materials, Journal Name: Nature Materials Journal Issue: 3 Vol. 22; ISSN 1476-1122

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

References (60)

A Systems Analysis Identifies a Feedforward Inflammatory Circuit Leading to Lethal Influenza Infection Brandes, Marlène; Klauschen, Frederick; Kuchen, Stefan Cell, Vol. 154, Issue 1 https://doi.org/10.1016/j.cell.2013.06.013	journal	July 2013
Germinal Center Selection and the Antibody Response to Influenza Victora, Gabriel D.; Wilson, Patrick C. Cell, Vol. 163, Issue 3 https://doi.org/10.1016/j.cell.2015.10.004	journal	October 2015
Comprehensive Integration of Single-Cell Data Stuart, Tim; Butler, Andrew; Hoffman, Paul Cell, Vol. 177, Issue 7 https://doi.org/10.1016/j.cell.2019.05.031	journal	June 2019
Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 Walls, Alexandra C.; Fiala, Brooke; Schäfer, Alexandra Cell, Vol. 183, Issue 5 https://doi.org/10.1016/j.cell.2020.10.043	journal	November 2020
Immunodominance: A pivotal principle in host response to viral infections Akram, Ali; Inman, Robert D. Clinical Immunology, Vol. 143, Issue 2 https://doi.org/10.1016/j.clim.2012.01.015	journal	May 2012
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 Gonzalez-Lopez, Antonio; Oostendorp, Jaap; Koernicke, Thomas Clinical Immunology, Vol. 209 https://doi.org/10.1016/j.clim.2019.108275	journal	December 2019
Self-assembling protein nanoparticles in the design of vaccines López-Sagaseta, Jacinto; Malito, Enrico; Rappuoli, Rino Computational and Structural Biotechnology Journal, Vol. 14 https://doi.org/10.1016/j.csbj.2015.11.001	journal	January 2016
Germinal Center B Cell Dynamics Mesin, Luka; Ersching, Jonatan; Victora, Gabriel D. Immunity, Vol. 45, Issue 3 https://doi.org/10.1016/j.immuni.2016.09.001	journal	September 2016
Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens Abbott, Robert K.; Lee, Jeong Hyun; Menis, Sergey Immunity, Vol. 48, Issue 1 https://doi.org/10.1016/j.immuni.2017.11.023	journal	January 2018
Exploration of Cell Development Pathways through High-Dimensional Single Cell Analysis in Trajectory Space Dermadi, Denis; Bscheider, Michael; Bjegovic, Kristina iScience, Vol. 23, Issue 2 https://doi.org/10.1016/j.isci.2020.100842	journal	February 2020
Adsorption of a synthetic TLR7/8 ligand to aluminum oxyhydroxide for enhanced vaccine adjuvant activity: A formulation approach Fox, Christopher B.; Orr, Mark T.; Van Hoeven, Neal Journal of Controlled Release, Vol. 244 https://doi.org/10.1016/j.jconrel.2016.11.011	journal	December 2016
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 Innis, Bruce L.; Berlanda Scorza, Francesco; Blum, Jeremy S. Vaccine, Vol. 37, Issue 35 https://doi.org/10.1016/j.vaccine.2019.06.080	journal	August 2019
Synthesis and Biomedical Applications of Functional Poly(α-hydroxy acids) via Ring-Opening Polymerization of O-Carboxyanhydrides Yin, Qian; Yin, Lichen; Wang, Hua Accounts of Chemical Research, Vol. 48, Issue 7 https://doi.org/10.1021/ar500455z	journal	June 2015
Drug-Initiated Ring-Opening Polymerization of O-Carboxyanhydrides for the Preparation of Anticancer Drug–Poly(O-carboxyanhydride) Nanoconjugates Yin, Qian; Tong, Rong; Xu, Yunxiang Biomacromolecules, Vol. 14, Issue 3 https://doi.org/10.1021/bm301999c	journal	February 2013
Programming the magnitude and persistence of antibody responses with innate immunity Kasturi, Sudhir Pai; Skountzou, Ioanna; Albrecht, Randy A. Nature, Vol. 470, Issue 7335 https://doi.org/10.1038/nature09737	journal	February 2011
Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions Chung, Yeonseok; Tanaka, Shinya; Chu, Fuliang Nature Medicine, Vol. 17, Issue 8 https://doi.org/10.1038/nm.2426	journal	July 2011
Key roles of adjuvants in modern vaccines Reed, Steven G.; Orr, Mark T.; Fox, Christopher B. Nature Medicine, Vol. 19, Issue 12 https://doi.org/10.1038/nm.3409	journal	December 2013
Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection Yassine, Hadi M.; Boyington, Jeffrey C.; McTamney, Patrick M. Nature Medicine, Vol. 21, Issue 9 https://doi.org/10.1038/nm.3927	journal	August 2015
Engineering synthetic vaccines using cues from natural immunity Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L. Nature Materials, Vol. 12, Issue 11 https://doi.org/10.1038/nmat3775	journal	October 2013
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A. Nature Protocols, Vol. 4, Issue 1 https://doi.org/10.1038/nprot.2008.211	journal	December 2008
Emerging concepts in the science of vaccine adjuvants Pulendran, Bali; S. Arunachalam, Prabhu; O’Hagan, Derek T. Nature Reviews Drug Discovery, Vol. 20, Issue 6 https://doi.org/10.1038/s41573-021-00163-y	journal	April 2021
A guide to vaccinology: from basic principles to new developments Pollard, Andrew J.; Bijker, Else M. Nature Reviews Immunology, Vol. 21, Issue 2 https://doi.org/10.1038/s41577-020-00479-7	journal	December 2020
SARS-CoV-2 vaccines in development Krammer, Florian Nature, Vol. 586, Issue 7830 https://doi.org/10.1038/s41586-020-2798-3	journal	September 2020
Quadrivalent influenza nanoparticle vaccines induce broad protection Boyoglu-Barnum, Seyhan; Ellis, Daniel; Gillespie, Rebecca A. Nature, Vol. 592, Issue 7855 https://doi.org/10.1038/s41586-021-03365-x	journal	March 2021
Adjuvanting a subunit COVID-19 vaccine to induce protective immunity Arunachalam, Prabhu S.; Walls, Alexandra C.; Golden, Nadia Nature, Vol. 594, Issue 7862 https://doi.org/10.1038/s41586-021-03530-2	journal	April 2021
Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization Planas, Delphine; Veyer, David; Baidaliuk, Artem Nature, Vol. 596, Issue 7871 https://doi.org/10.1038/s41586-021-03777-9	journal	July 2021
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion Mlcochova, Petra; Kemp, Steven A.; Dhar, Mahesh Shanker Nature, Vol. 599, Issue 7883 https://doi.org/10.1038/s41586-021-03944-y	journal	September 2021
Modeling human adaptive immune responses with tonsil organoids Wagar, Lisa E.; Salahudeen, Ameen; Constantz, Christian M. Nature Medicine, Vol. 27, Issue 1 https://doi.org/10.1038/s41591-020-01145-0	journal	January 2021
T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers Arunachalam, Prabhu S.; Charles, Tysheena P.; Joag, Vineet Nature Medicine, Vol. 26, Issue 6 https://doi.org/10.1038/s41591-020-0858-8	journal	May 2020
New SARS-CoV-2 Variants — Clinical, Public Health, and Vaccine Implications Abdool Karim, Salim S.; de Oliveira, Tulio New England Journal of Medicine, Vol. 384, Issue 19 https://doi.org/10.1056/NEJMc2100362	journal	May 2021
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 Wille-Reece, Ulrike; Flynn, Barbara J.; Loré, Karin Proceedings of the National Academy of Sciences, Vol. 102, Issue 42 https://doi.org/10.1073/pnas.0507484102	journal	October 2005
Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants Maisonneuve, Charles; Bertholet, Sylvie; Philpott, Dana J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 34 https://doi.org/10.1073/pnas.1400478111	journal	August 2014
Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection Mallajosyula, V. V. A.; Citron, M.; Ferrara, F. Proceedings of the National Academy of Sciences, Vol. 111, Issue 25 https://doi.org/10.1073/pnas.1402766111	journal	June 2014
Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans Ellebedy, A. H.; Krammer, F.; Li, G. -M. Proceedings of the National Academy of Sciences, Vol. 111, Issue 36 https://doi.org/10.1073/pnas.1414070111	journal	August 2014
Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis Yin, Qian; Tang, Li; Cai, Kaimin Proceedings of the National Academy of Sciences, Vol. 113, Issue 32 https://doi.org/10.1073/pnas.1603316113	journal	July 2016
B Cell Response to Vaccination Luo, Wei; Yin, Qian Immunological Investigations, Vol. 50, Issue 7 https://doi.org/10.1080/08820139.2021.1903033	journal	March 2021
Advances in aluminum hydroxide-based adjuvant research and its mechanism He, Peng; Zou, Yening; Hu, Zhongyu Human Vaccines & Immunotherapeutics, Vol. 11, Issue 2 https://doi.org/10.1080/21645515.2014.1004026	journal	February 2015
Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates Wille-Reece, Ulrike; Flynn, Barbara J.; Loré, Karin Journal of Experimental Medicine, Vol. 203, Issue 5 https://doi.org/10.1084/jem.20052433	journal	April 2006
Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A. Nucleic Acids Research, Vol. 37, Issue 1 https://doi.org/10.1093/nar/gkn923	journal	November 2008
An improved nonparametric lower bound of species richness via a modified good-turing frequency formula: An Improved Nonparametric Lower Bound of Species Richness Chiu, Chun-Huo; Wang, Yi-Ting; Walther, Bruno A. Biometrics, Vol. 70, Issue 3 https://doi.org/10.1111/biom.12200	journal	June 2014
Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem Havenar-Daughton, Colin; Lee, Jeong Hyun; Crotty, Shane Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12512	journal	January 2017
Linking signaling and selection in the germinal center Shlomchik, Mark J.; Luo, Wei; Weisel, Florian Immunological Reviews, Vol. 288, Issue 1 https://doi.org/10.1111/imr.12744	journal	March 2019
Factors in B cell competition and immunodominance Abbott, Robert K.; Crotty, Shane Immunological Reviews, Vol. 296, Issue 1 https://doi.org/10.1111/imr.12861	journal	June 2020
A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen Impagliazzo, A.; Milder, F.; Kuipers, H. Science, Vol. 349, Issue 6254 https://doi.org/10.1126/science.aac7263	journal	August 2015
mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation Sinclair, Charles; Bommakanti, Gayathri; Gardinassi, Luiz Science, Vol. 357, Issue 6355 https://doi.org/10.1126/science.aaj2155	journal	September 2017
3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope–specific plasma cells and humoral immunity in nonhuman primates Kasturi, Sudhir Pai; Rasheed, Mohammed Ata Ur; Havenar-Daughton, Colin Science Immunology, Vol. 5, Issue 48 https://doi.org/10.1126/sciimmunol.abb1025	journal	June 2020
A yeast-expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates Pino, Maria; Abid, Talha; Pereira Ribeiro, Susan Science Immunology, Vol. 6, Issue 61 https://doi.org/10.1126/sciimmunol.abh3634	journal	July 2021
MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines Khurana, Surender; Verma, Nitin; Yewdell, Jonathan W. Science Translational Medicine, Vol. 3, Issue 85 https://doi.org/10.1126/scitranslmed.3002336	journal	June 2011
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 Kasturi, Sudhir Pai; Kozlowski, Pamela A.; Nakaya, Helder I. Journal of Virology, Vol. 91, Issue 4 https://doi.org/10.1128/JVI.01844-16	journal	February 2017
Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain Steel, John; Lowen, Anice C.; Wang, Taia T. mBio, Vol. 1, Issue 1 https://doi.org/10.1128/mBio.00018-10	journal	May 2010
An Intranasal Virus-Like Particle Vaccine Broadly Protects Mice from Multiple Subtypes of Influenza A Virus Schwartzman, Louis M.; Cathcart, Andrea L.; Pujanauski, Lindsey M. mBio, Vol. 6, Issue 4 https://doi.org/10.1128/mBio.01044-15	journal	September 2015
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 Spassova, Ivelina; Ugurel, Selma; Terheyden, Patrick Clinical Cancer Research, Vol. 26, Issue 9 https://doi.org/10.1158/1078-0432.CCR-19-2244	journal	May 2020
Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem Tan, Hyon-Xhi; Jegaskanda, Sinthujan; Juno, Jennifer A. Journal of Clinical Investigation, Vol. 129, Issue 2 https://doi.org/10.1172/JCI123366	journal	January 2019
Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques Petitdemange, Caroline; Kasturi, Sudhir Pai; Kozlowski, Pamela A. JCI Insight, Vol. 4, Issue 4 https://doi.org/10.1172/jci.insight.126047	journal	February 2019
MyD88: a central player in innate immune signaling Deguine, Jacques; Barton, Gregory M. F1000Prime Reports, Vol. 6 https://doi.org/10.12703/P6-97	journal	November 2014
Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge Om, Kier; Paquin-Proulx, Dominic; Montero, Maria PLOS Pathogens, Vol. 16, Issue 9 https://doi.org/10.1371/journal.ppat.1008764	journal	September 2020
The use of Toll-like receptor 7/8 agonists as vaccine adjuvants Vasilakos, John P.; Tomai, Mark A. Expert Review of Vaccines, Vol. 12, Issue 7 https://doi.org/10.1586/14760584.2013.811208	journal	July 2013
Influenza virus-like particle vaccines Haynes, Joel R. Expert Review of Vaccines, Vol. 8, Issue 4 https://doi.org/10.1586/erv.09.8	journal	April 2009
Reproducibility of Methods to Detect Differentially Expressed Genes from Single-Cell RNA Sequencing Mou, Tian; Deng, Wenjiang; Gu, Fengyun Frontiers in Genetics, Vol. 10 https://doi.org/10.3389/fgene.2019.01331	journal	January 2020
Public Clonotypes and Convergent Recombination Characterize the Naïve CD8+ T-Cell Receptor Repertoire of Extremely Preterm Neonates Carey, Alison J.; Hope, Jennifer L.; Mueller, Yvonne M. Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.01859	journal	December 2017

Similar Records

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses

Journal Article · Sun Apr 02 20:00:00 EDT 2023 · Cell Reports · OSTI ID:2423518

Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine

Journal Article · Tue May 09 20:00:00 EDT 2023 · Science Translational Medicine · OSTI ID:1989359

Related Subjects

60 APPLIED LIFE SCIENCES
adjuvants
drug delivery

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2

Citation Formats

References (60)

Similar Records

Related Subjects