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