mRNA Vaccine Delivery Using Lipid Nanoparticles

Reichmuth, Andreas M.; Oberli, Matthias A.; Jaklenec, Ana; Langer, Robert; Blankschtein, Daniel

doi:10.4155/tde-2016-0006

Cited by 478 publications

(521 citation statements)

References 149 publications

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“…and D.W., unpublished observations). Great progress has been made in developing similarly designed complexing reagents for safe and effective in vivo use, and these are discussed in detail in several recent reviews 10,11,79,80 . Cationic lipids and polymers, including dendrimers, have become widely used tools for mRNA administration in the past few years.…”

Section: Recent Advances In Mrna Vaccine Technologymentioning

confidence: 99%

See 1 more Smart Citation

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

3,098

3,330

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mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

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Section: Recent Advances In Mrna Vaccine Technologymentioning

confidence: 99%

“…As discussed above, numerous delivery formulations have been developed to facilitate mRNA uptake, increase protein translation and protect mRNA from RNases 10,11,79,80 . Another important issue is the biodistribution of mRNA vaccines after systemic delivery.…”

Section: Mrna Cancer Vaccinesmentioning

confidence: 99%

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

3,098

3,330

View full text Add to dashboard Cite

show abstract

“…Data are representative of two independent experiments. 20 IFNα IFNγ IL12P70 IL15/IL15R IL17A IL18 IL1A IL2 IL22 IL23 IL27 IL28 IL3 IL31 IL4 IL5 IL6 IL9 IL10 MCSF MCP1 MCP3 MIP1A MIP1B MIP2 RANTES TNFα TGFβ 1 2 3 Fold change over ctr. treated In situ therapy with a combination of Ox40lþCd80/86 induces local activation of T cells and secretion of proinflammatory cytokines that can be traced to the local draining lymph node and the distal nontreated tumor.…”

Section: In Situ Therapy With a Combination Of Ox40l And Cd80/86 Incimentioning

confidence: 99%

“…Ideally, mRNA prodrugs and the vectors that deliver them would demonstrate minimal inherent immunogenic properties but convey target-specific immunogenicity by the introduction of tumor-specific antigens or immunostimulatory modulators. However, the most common LNP-based delivery vehicles are inherently immunogenic (17,18), which can trigger undesirable off-target effects such as a vaccination effect against the delivered mRNA-encoded immunostimulatory molecules it delivers (19,20). Regardless, nanoparticle-based approaches for transient mRNA expression of immunomodulatory genes within the tumor microenvironment represent a novel, safe, and versatile immunotherapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

et al. 2019

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Localized expression of effector molecules can initiate antitumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic antitumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for costimulatory and immune-modulating factors. Intratumoral injection of the CART-mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local antitumor effect. Using a twotumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic antitumor response, curing both tumors. The combination of Ox40l-, Cd80-, and Cd86-encoding mRNA resulted in the local upregulation of proinflammatory cytokines, robust local T-cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic antitumor immunity from a single localized injection.Significance: The mRNA-CART system is a highly effective delivery platform for delivering immunostimulatory genes into the tumor microenvironment for potential therapeutic development.

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“…This pathway could potentially lower the doses needed for mRNA vaccines while retaining the immunogenicity observed with DNA vaccines. ZIKV prM-ENV mRNA was encapsulated in a lipid nanoparticle for delivery and stability 53 , and immunization of both mice and monkeys with this vaccine induced high levels of neutralizing antibodies that protected against ZIKV infection 54,55 . In mouse pregnancy models, these mRNA vaccines prevented fetal demise, whereas fetal resorption was observed in non-immunized infected pregnant mice.…”

Section: Vaccines In Clinical Trialsmentioning

confidence: 99%

Zika virus vaccines

2018

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The recent epidemic of Zika virus (ZIKV) in the Americas has revealed the devastating consequences of ZIKV infection, particularly in pregnant women. Congenital Zika syndrome, characterized by malformations and microcephaly in neonates as well as developmental challenges in children, highlights the need for the development of a safe and effective vaccine. Multiple vaccine candidates have been developed and have shown promising results in both animal models and phase I clinical trials. However, important challenges remain for clinical development of these vaccines. In this Progress, we discuss recent preclinical studies and lessons learned from first in-human clinical trials with ZIKV vaccines.

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mRNA Vaccine Delivery Using Lipid Nanoparticles

Cited by 478 publications

References 149 publications

mRNA vaccines — a new era in vaccinology

mRNA vaccines — a new era in vaccinology

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

Zika virus vaccines

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