4. RNA based vaccines
Though DNA vaccines avoid the anti-vector immunity, long term existence in cells might produce excessive antigens, which might provoke overactive immune responses and exhaust T cells . Thus, another kind of nucleic acid-based vaccines, RNA vaccines, were developed by directly delivering mRNA into cells for the prevention and therapy of diseases. Without the need to entry into cell nucleus, RNA vaccines mainly function in cytoplasm, which might have higher efficiency in delivery .
RNA vaccines can be classified into 2 categories: conventional mRNA-based vaccines and self-amplifying mRNA vaccines (SAM, also termed replicons) (Fig. 9) . Upon entry into cells, conventional RNA vaccines directly generate antigens with nutrients and materials of host cells. On the contrary, SAM vaccines generate antigens by several steps (Fig. 16). SAM can self-replicate in host cells, thus they can mediate high expression levels of antigen. Due to no expression of structural proteins, no virion particle can be produced.
Besides the common immune responses induced by endogenous antigens, mRNA vaccine can elicit a robust type I IFN response, which facilitates CD8+ T cell cytolytic capacity and promotes eradication of infected cells . However, some adverse effects are also observed. For example, specific single mutations in nsP1 sequence of alphaviruses, such as A533I, induce elevated Type I IFN expression, but decrease the expression level of antigen and vaccine immunity [144, 145]. To improve the efficacy of RNA vaccines, several strategies are applied: ① Modify or optimize the vaccine backbone, such as 5ʹ cap, poly (A) tail, codon optimization; ② Delivery systems (naked mRNA, formulation with liposomes, lipoplexes, polyplexes, particulate carrier-mediated, electroporation, and gene gun  ) and route of administration (such as intradermal  or intratumor administration ); ③ supplementation with small immunomodulatory molecules can also help improve the immune responses provoked by RNA vaccines, such as dexamethasone .
As a novel kind of vaccine, RNA vaccines have many advantages: ① Induction of humoral immune responses and cell immune responses; ② Provoke stronger immunity than DNA vaccines; ③ Avoid the anti-vector immunity; ④ Mediate transient expression of antigen; ⑤ No integration into host genome. To date, numerous mRNA vaccines have been translated into clinical trials, and several of them are listed in the following Table 9 .
|Melanoma||NY-ESO-1, MAGE-A3, tyrosinase and TPTE||Intravenous||Phase I||IFNα and strong antigen-specific T-cell responses were induced|||
|Non-small cell lung carcinoma (NSCLC)||NY-ESO-1, MAGEC1, MAGEC2, BIRC5, TPBG, and MUC1||Intradermal||Phase I||Improved survival|||
|Melanoma||Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21||Intradermal||Phase II||Vaccines are feasible and safe, and induce immune response|||
|Melanoma||Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 22||Intradermal||Phase I/II||An increase in antitumor humoral immune response was observed in some patient|||
|Renal cell carcinoma (RCC)||Tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1)||Intradermal||Phase I/II||Induce CD8+ and CD4+ immune Responses|||
|Renal cell carcinoma (RCC)||MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1||Intradermal||Phase I/II||A clear correlation was observed between survival and immunological responses to TAAs|||
|Rabies||Rabies virus glycoprotein (CV7201)||Intradermal or intramuscular||Phase I||Boostable functional antibodies against a viral antigen was observed when administered with a needle-free device|||
|Flu||Hemagglutinin (HA) proteins||Intramuscular||Phase I||Protective immunogenicity with acceptable tolerability profiles were induced|||
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