Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses
Open accessAbstract
Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.
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Modifications to the spike protein are intended to reduce the innate immune response by inhibiting proinflammatory cytokines, while the lipid nanoparticle vehicle/EV for the mRNA acts as an adjuvant to enhance the immune response.
“Modifications to the spike protein are intended to reduce the innate immune response by inhibiting proinflammatory cytokines, while at the same time, the lipid nanoparticle vehicle/EV for the mRNA acts as an adjuvant to enhance the immune response. 194-196”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [195]
The Discussion (page unavailable) says the mRNA is nucleoside-modified to reduce inflammation caused by innate sensing; it does not attribute that effect to modifications of the spike protein or specify inhibition of proinflammatory cytokines. The Results section (page unavailable) demonstrates that the LNP formulation has adjuvant activity and enhances vaccine responses in mice, supporting the second part of the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAdjuvant activity of the LNP critically relies on IL-6 and its constituent ionizable lipid.
“Adjuvant activity of the LNP critically relies on IL-6 and its constituent ionizable lipid.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [38]
LNP exerts potent stimulatory activity against T follicular helper cells and immune induction superior to AddaVax formulated vaccine.
“When used in mRNA and protein subunit vaccines, LNP exerts potent stimulatory activity against T follicular helper cell and the immune induction was superior to what induced by AddaVax formulated vaccine.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [38]
Potent immune responses from a single immunization of LNP loaded non-inflammatory nucleoside-modified mRNA was related to LNP adjuvanticity.
“Remarkably, potent immune responses from a single immunization of LNP loaded non-inflammatory nucleoside-modified mRNA was related to LNP adjuvanticity (38).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [38]
In combination with LNPs, modified mRNA is now the basis for the separate mRNA vaccine platform that has been proven most successful based on an optimal immune response originating from the compromise between LNP adjuvant function and modified mRNA, allowing improved efficacy and safety.
“In combination with LNPs, modified mRNA is now the basis for the separate mRNA vaccine platform41,44 that has been proven as the most successful based on its optimal immune response originating from the compromise between LNP adjuvant function33 and modified mRNA, allowing improved efficacy and safety.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [33]
LNPs possess a potent adjuvant function, demonstrating beneficial effects in vaccine application.
“Moreover, it was recently found that LNPs possess a potent adjuvant function, which further demonstrates their beneficial effects in vaccine application.33”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [33]
LNP-driven adjuvant activity leads to induction of strong Tfh cell responses and humoral immunity, thus enhancing the efficacy of mRNA-based vaccines.
“This LNP-driven adjuvant activity leads to induction of strong Tfh cell responses and humoral immunity, thus enhancing the efficacy of mRNA-based vaccines.33”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [33]
The LNP component of LNP-mRNA vaccines has adjuvant activity that is dependent on its ionizable lipid component and IL-6 cytokine induction.
“Recently, it was found that the LNP component of LNP-mRNA vaccines has adjuvant activity, which is dependent on its ionizable lipid component and IL-6 cytokine induction.33”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [33]
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Flagged first, then by citations
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- Authors
- Alameh, M.-G., Tombácz, I., Bettini, E., Lederer, K., Ndeupen, S., Sittplangkoon, C., Wilmore, J. R., Gaudette, B. T., Soliman, O. Y., Pine, M., Hicks, P., Manzoni, T. B., Knox, J. J., Johnson, J. L., Laczkó, D., Muramatsu, H., Davis, B., Meng, W., Rosenfeld, A. M., Strohmeier, S., Lin, P. J. C., Mui, B. L., Tam, Y. K., Karikó, K., Jacquet, A., Krammer, F., Bates, P., Cancro, M. P., Weissman, D., Luning Prak, E. T., Allman, D., Igyártó, B. Z., Locci, M., & Pardi, N.
- Affiliations
- University of Pennsylvania (US)
- Thomas Jefferson University (US)
- Chulalongkorn University (TH)
- Icahn School of Medicine at Mount Sinai (US)
- Acuitas Therapeutics (Canada) (CA)
- BioNTech (Germany) (DE)
- Corresponding author
- Locci, Michela
- Pardi, Norbert
- ORCID
- Alameh, Mohamad-Gabriel
- Tombácz, István
- Bettini, Emily
- Lederer, Katlyn
- Sittplangkoon, Chutamath
- Wilmore, Joel R.
- Gaudette, Brian T.
- Soliman, Ousamah Y.
- Pine, Matthew
- Hicks, Philip
- Manzoni, Tomaz B.
- Knox, James J.
- Johnson, John L.
- Muramatsu, Hiromi
- Davis, Benjamin
- Meng, Wenzhao
- Rosenfeld, Aaron M.
- Strohmeier, Shirin
- Lin, Paulo J.C.
- Mui, Barbara L.
- Tam, Ying K.
- Karikó, Katalin
- Jacquet, Alain
- Krammer, Florian
- Bates, Paul
- Cancro, Michael P.
- Weissman, Drew
- Allman, David
- Igyártó, Botond Z.
- Locci, Michela
- Pardi, Norbert
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 54
- Issue
- 12
- Pages
- 2877-2892.e7
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC8566475
- OpenAlex
- W3209735640
- Cited by
- 775
- References
- 89
- Citations by year
- 2026: 155 · 2025: 221 · 2024: 181 · 2023: 132 · 2022: 82 · 2021: 4
- FWCI
- 37.14
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-06-14)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institute of Allergy and Infectious Diseases (R01-AI124429, R01AI123738, 1U19AI135902, R01AI153064, U19-AI142596, UM1-AI-144371, HHS-NIH-NIAID-BAA2018, R01AI146101)
- Icahn School of Medicine at Mount Sinai
- Children's Hospital of Philadelphia
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- lipid nanoparticles, vaccine adjuvants, mRNA vaccines, subunit vaccine, T follicular helper cells, germinal center B cells, long-lived plasma cells, memory B cells, humoral immune response, SARS-CoV-2, influenza virus, ionizable lipids, interleukin-6, MF59, AddaVax, MyD88, MAVS
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Adjuvants, Immunologic, Animals, B-Lymphocytes, T-Lymphocytes, Helper-Inducer, Humans, Liposomes, Mice, Inbred BALB C, Interleukin-6, Germinal Center, Protein Subunits, Adaptor Proteins, Signal Transducing, Mice, Nanoparticles, Immunity, Humoral, HEK293 Cells
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