An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo
Abstract
:1. Introduction
2. Structure of IVT mRNA for Improved Translation
3. Effect of Nucleoside Modification in Antigen Expression
4. Formulations of mRNA for In Vivo Drug Delivery
4.1. Protamine
Target mRNA | Stage | Findings | Ref. |
---|---|---|---|
β-gal and GFP | HeLa-K cells injected into B6 (H2) and BALB/c mice | Successful CTL response, dependent on injection site | [17] |
β-gal or CMV pp65 | Murine BM-DC | Stimulated mouse BM- DC: induced IL-6 and IL-12 release and up-regulation of CD86 | [44] |
β-gal, EGFP, or CMV pp65 | Human PBMC | Complexes induced release of strong IL-6 and TNF-α, stimulation of innate immunity and other APCs | [62] |
Melan-A, Tyrosinase, gp100, MAGE-A1, MAGE-A3, and Survivin | Individuals with metastatic melanoma | Raised frequency of immunosuppressive and vaccine-directed cellular immune response | [28] |
OVA (GgOVA), control vaccine (Ecβ-gal sh), PSMA (HsPSMA), and STEAP vaccine (HsSTEAP) | Rat (C57BL/6, BALB/c) | Showed antitumor by activating adaptive and innate immune systems, stimulation of toll-like receptor 7 (TLR-7), ability to inhibit established tumors, induction of two component mRNA vaccine | [64] |
Ovalbumin with radiation, two component vaccine | Rat (C57BL/6) | mRNA immunotherapy and tumor irradiation act synergistically to eradicate established tumor (Lewis lung cancer) | [69] |
Rabies glycoprotein (RABV-G) | Rat (C57BL/6, BALB/c) and domestic pigs | Induced potent neutralizing antibody superior to licensed vaccines, induced lethal challenge against rabies, induce homeostasis | [68] |
RNActive Ovalbumin, luciferase fused rabies glycoprotein, two component vaccine | Rat (C57BL/6, BALB/c) | Vaccine taken up by leukocyte and non-leukocytic cells, represented by APCs, transport to draining lymph nodes (dLNs), T-cell proliferation, immune cell activations, and induction of adaptive immunity | [70] |
4.2. Lipid Nanoparticles
Target mRNA | Lipid Nanoparticle Contents | Stage | Findings | Ref. |
---|---|---|---|---|
Luciferase | DOTAP liposomes covered with apatite nanoparticles | HeLa | Along with ARCA had more than 100-fold increase compared to DOTAP, proportion not assessed | [91] |
Luciferase | DOTAP liposomes protected with apatite nanoparticles | HeLa NIH 3T3 | 9–14 fold improved compared to mRNA liposome alone, proportion not determined | [90] |
Luciferase | Fibronectin associated DOTAP liposomes protected with apatite nanoparticles | HeLa | Fn-DOTAP-apatite complex showed 50-fold increase than DOTAP alone, proportion not assessed | [75] |
TriMix mRNA encoding CD40-ligand, CD70 and TLR | DOTAP/DOPE/DSPE-PEG-2000-biotin | Primary murine bone marrow-derived DC from C57BL/6 mice | 19% improved | [102] |
Luciferase | DOTAP/DOPE/DSPE-PEG-2000-biotin lipoplex loaded microbubbles | DC primary cultures from the bone marrow of C57BL/6 mice | 24% improved | [103] |
EGFP | Lipofectamine 2000 and TransIT | Neurospheres from subventricular zone of adult C57BL/6 mice | 40–50% improved | [104] |
GFP and luciferase | MLRI/DOPE and TransFast | CHO, NIH3T3 | >50% improved >40% improved | [105] |
EGFP, B-16 | Novel cationic lipids: X2, S1, S2, S3, 2X3, and 2D3 with DOPE | DC cells cultured from the bone marrow of C57BL/6 mice | Up to 47% of DC progenitors Up to 57% of immature DCs | [106] |
Herpes simplex virus 1-thymidine kinase | DOTAP-cholesterol liposome with DSPE-PEG and DSPE-PEG-AA, encapsulating protamine-mRNA cores | NCI-H460 xenograft | 68~78% improved | [31] |
GFP, Luciferase and CXCR4 | DOTAP/DOPE | HeLa | ~80% improved | [107] |
Luciferase and GFP | Stemfect | JAWS II DC2.4 | 80%; >97%; >50% and >60% | [108] |
Photinus pyralis luciferase (PpLuc), rabies glycoprotein (RABV-G), influenza | (70~100 nm) lipid nanoparticles prepared by ionizable amino lipid, PEGylated lipid, phospholipid, and cholesterol | BALB/c, pigs | Lipid formulated mRNA vaccine induced protective antibody titers; boosted and stable for 1 year | [92] |
Photinus pyralis luciferase (PpLuc), Epo (mouse, pig and maque) | Inonizable cataionic lipid/phosphatidylcholine/cholesterol/PEG; 50:10:38.5:1.5 mol/mol | HeLa, BALB/c, pigs, monkeys | Induced high mRNA expression and elicited significant physiological response in mice and nonhuman primates | [22] |
mRNA encoding hemagglutinin of H10N8 (A/Jiangxi-Donghu-/346/2013) or H7N9 (A/Anhui/1/2013) influenza virus | Ionizable lipid: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC): cholesterol: PEG-lipid (50:10:38.5:1.5) | HeLa, BALB/c, ferrets, cynomolgus monkeys, human | Induced rapid and robust immune responses in ferrets, mice, and NHPs; single dose of mRNA encoding H7N9 saved mice against lethal challenge and decreased lung viral titers in ferrets; elicited robust immune response in humans with mild or moderate adversity | [93] |
Luciferase, Ovalbumin (OVA) expressing B16F10 mouse melanoma | Lipid nanoparticles library | C57BL/6J | Optimized LNPs showed transfection in various immune cells; stimulation of a robust CD8+ T-cell response after single immunization; greater survival rate in a transgenic mice melanoma | [57] |
Firefly luciferase, Ovalbumin (OVA) expressing B16F10 mouse melanoma, papilloma E7 protein | Multi-dimensional over 1000 lipid nanoparticles consisting of heterocyclic ring | HeLa, bone marrow-derived dendritic cells and bone marrow-derived and peritoneal macrophages, Ai14 mice model | Top-performing lipid elicited a robust immune activation, prevented tumor progression and long-lasting survival in human papillomavirus E7 and melanoma in the in vivo tumor model | [95] |
4.3. Electroporation Plus Nanoparticles Formulation
5. Challenges and Safety Issues in the Development of mRNA-Based Vaccines against Novel Antigens
Antigen/Study Identifier/Phase | Subjects/Numbers | Route | Major Findings | Ref. |
---|---|---|---|---|
Rabies glycoprotein/NCT02241135/Phase I | 18–40 years (volunteers), 101 healthy individuals | ID and IM | 94% of ID and 97% of IM vaccinated populations received severe injection site reactions, and 78% ID and 78% of IM injected peoples demonstrated severe systemic reactions, induce antibody response when administered with a needle free device, safe with a tolerability profile | [142] |
Melan-A, Tyrosinase, gp100, MAGE-A1, MAGE-A3, Survivin/NCT00204607/Phase I/II | 18–80 years, 21 patients with metastatic melanoma | ID | No adversity was observed more than grade II, feasible and safe, rate of Foxp3+/CD4+ regulatory T lymphocytes were reduced significantly upon mRNA plus keyhole limpet hemocyanin (KLH) injection, CD11b+HLA-DR lo monocytes (myeloid suppressor cells) were decreased in the patients without KLH addition | [28] |
NY-ESO-1, MAGEC1, MAGEC2, 5T4, Survivin, MUC1/NCT01915524/ Phase 1b | ≥18 years, 19 patients with NSCLC | ID | No serious toxicity was observed, only 7% patients experienced grade >3 related adversity, antigen-mediated immune induction was seen in more than 2/3 of patients | [143] |
HIV-1/NCT00672191/Phase II | 18 to 60 years, 59 participants | ID | Develop immune control of HIV-1 reproduction | [144] |
Spike protein (COVID-19)/NCT04470427/Phase II | 18 to 99 years, 30,000 participants | IM | Ongoing | [145] |
Spike protein/NCT04283461/Phase I | 56 to 70 years, 40 healthy adults | IM | Mild or moderate adversity was observed, 100 μg mRNA produced higher virus neutralizing-antibody titers than 25 μg | [129] |
Spike protein/NCT04368728/Phase I and II | 18 to 55 years, 45 adults | IM | Adversity was dose-dependent, transient, mostly mild to moderate | [146] |
Spike protein/NCT04283461/Phase I | 18 to 55 years, 45 healthy adults | IM | This vaccine candidate induced immune responses against COVID-19 in all populations, and no trial-limiting safety issues were detected | [147] |
Spike protein/NCT04566276/Phase I and II | 65 to 75 years, 600 healthy adults | IM | Ongoing | [148] |
Spike protein/NCT04515147/Phase II | 18 to 60 years, 691 participants | IM | Ongoing |
6. Future Direction and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Rahman, M.M.; Zhou, N.; Huang, J. An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo. Vaccines 2021, 9, 244. https://doi.org/10.3390/vaccines9030244
Rahman MM, Zhou N, Huang J. An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo. Vaccines. 2021; 9(3):244. https://doi.org/10.3390/vaccines9030244
Chicago/Turabian StyleRahman, Md. Motiar, Nan Zhou, and Jiandong Huang. 2021. "An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo" Vaccines 9, no. 3: 244. https://doi.org/10.3390/vaccines9030244
APA StyleRahman, M. M., Zhou, N., & Huang, J. (2021). An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo. Vaccines, 9(3), 244. https://doi.org/10.3390/vaccines9030244