Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

Xuexiang Han; Mohamad Gabriel Alameh; Kamila Butowska; James J. Knox; Kendall Lundgreen; Majed Ghattas; Ningqiang Gong; Lulu Xue; Ying Xu; Marc Lavertu; Paul Bates; Junchao Xu; Guangjun Nie; Yi Zhong; Drew Weissman; Michael J. Mitchell

doi:10.1038/s41565-023-01404-4

Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

Xuexiang Han, Mohamad Gabriel Alameh, Kamila Butowska, James J. Knox, Kendall Lundgreen, Majed Ghattas, Ningqiang Gong, Lulu Xue, Ying Xu, Marc Lavertu, Paul Bates, Junchao Xu, Guangjun Nie, Yi Zhong, Drew Weissman, Michael J. Mitchell

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20 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1105-1114
Number of pages	10
Journal	Nature Nanotechnology
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/s41565-023-01404-4
State	Published - Sep 2023

Keywords

Animals
Humans
Mice
COVID-19 Vaccines
SARS-CoV-2/genetics
COVID-19/prevention & control
Adjuvants, Immunologic/pharmacology
RNA, Messenger/genetics
mRNA Vaccines
Nanoparticles

ASJC Scopus subject areas

Condensed Matter Physics
Bioengineering
Atomic and Molecular Physics, and Optics
Materials Science(all)
Electrical and Electronic Engineering
Biomedical Engineering

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10.1038/s41565-023-01404-4

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Han, X., Alameh, M. G., Butowska, K., Knox, J. J., Lundgreen, K., Ghattas, M., Gong, N., Xue, L., Xu, Y., Lavertu, M., Bates, P., Xu, J., Nie, G., Zhong, Y., Weissman, D., & Mitchell, M. J. (2023). Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nature Nanotechnology, 18(9), 1105-1114. https://doi.org/10.1038/s41565-023-01404-4

Han, X, Alameh, MG, Butowska, K, Knox, JJ, Lundgreen, K, Ghattas, M, Gong, N, Xue, L, Xu, Y, Lavertu, M, Bates, P, Xu, J, Nie, G, Zhong, Y, Weissman, D & Mitchell, MJ 2023, 'Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines', Nature Nanotechnology, vol. 18, no. 9, pp. 1105-1114. https://doi.org/10.1038/s41565-023-01404-4

@article{31f9981885564e76aa6145882112c69c,

title = "Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines",

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.",

keywords = "Animals, Humans, Mice, COVID-19 Vaccines, SARS-CoV-2/genetics, COVID-19/prevention & control, Adjuvants, Immunologic/pharmacology, RNA, Messenger/genetics, mRNA Vaccines, Nanoparticles",

author = "Xuexiang Han and Alameh, {Mohamad Gabriel} and Kamila Butowska and Knox, {James J.} and Kendall Lundgreen and Majed Ghattas and Ningqiang Gong and Lulu Xue and Ying Xu and Marc Lavertu and Paul Bates and Junchao Xu and Guangjun Nie and Yi Zhong and Drew Weissman and Mitchell, {Michael J.}",

note = "Funding Information: M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director{\textquoteright}s New Innovator Award (DP2 TR002776), a US National Science Foundation CAREER Award (CBET-2145491), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET) and a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI). K.B. acknowledges support from the Polish National Agency for Academic Exchange (number PNN/IWA/2019/00057, Poland). The authors thank S. Steimle from the Beckman Center for Cryo Electron Microscopy at the University of Pennsylvania for help in characterizing the morphology of LNPs. The authors acknowledge the Cell Center Services Facility at the University of Pennsylvania for assistance with the LAL test. The authors thank L. Chen, M. A. Eldabbas and E. Maddox of the Human Immunology Core at the University of Pennsylvania for providing human monocytes, who are supported by NIH P30 AI045008 and P30 CA016520. Elements of Figs. , , and created with BioRender.com. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = sep,

doi = "10.1038/s41565-023-01404-4",

language = "English (US)",

volume = "18",

pages = "1105--1114",

journal = "Nature Nanotechnology",

issn = "1748-3387",

publisher = "Nature Publishing Group",

number = "9",

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T1 - Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

AU - Han, Xuexiang

AU - Alameh, Mohamad Gabriel

AU - Butowska, Kamila

AU - Knox, James J.

AU - Lundgreen, Kendall

AU - Ghattas, Majed

AU - Gong, Ningqiang

AU - Xue, Lulu

AU - Xu, Ying

AU - Lavertu, Marc

AU - Bates, Paul

AU - Xu, Junchao

AU - Nie, Guangjun

AU - Zhong, Yi

AU - Weissman, Drew

AU - Mitchell, Michael J.

N1 - Funding Information: M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a US National Science Foundation CAREER Award (CBET-2145491), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET) and a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI). K.B. acknowledges support from the Polish National Agency for Academic Exchange (number PNN/IWA/2019/00057, Poland). The authors thank S. Steimle from the Beckman Center for Cryo Electron Microscopy at the University of Pennsylvania for help in characterizing the morphology of LNPs. The authors acknowledge the Cell Center Services Facility at the University of Pennsylvania for assistance with the LAL test. The authors thank L. Chen, M. A. Eldabbas and E. Maddox of the Human Immunology Core at the University of Pennsylvania for providing human monocytes, who are supported by NIH P30 AI045008 and P30 CA016520. Elements of Figs. , , and created with BioRender.com. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

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KW - Humans

KW - Mice

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KW - SARS-CoV-2/genetics

KW - COVID-19/prevention & control

KW - Adjuvants, Immunologic/pharmacology

KW - RNA, Messenger/genetics

KW - mRNA Vaccines

KW - Nanoparticles

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JO - Nature Nanotechnology

JF - Nature Nanotechnology

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ER -

Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

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