13.2. RNA-based vaccine
RNA vaccines providing rapid and cell-free platform for manufacturing viral antigens using the encoding mRNA in the core of lipid nanoparticle (LNP) covering. LNP content of such vaccines can enhance human immune responses without the need of extra adjuvants [119, 122]. Also, the lipid covering easily transports the mRNA into the cytoplasm of the cells, and unlike protein subunit vaccines facilitating effective protein translation and post-translational modifications. Besides, in vitro transcription is employed for pathogen mRNA achievement, so there is no risk of transmitting infectious agents or microbial components. Remarkable safety and efficacy, free risk of anti-vector immune responses, prompt and cost-effective production along with the possibility of repeated administration are some of the advantages of mRNA-based over other types of vaccines [123] that make them more attractive in COVID-19 vaccine researches. Generally, the conventional mRNA and the novel self- replicating and transcribing RNA (replicon) vaccines constitute the two major classes of RNA-based vaccines. In conventional strategy, the immunogenic viral protein is produced directly from the transcript included in the vaccine formulation, while replicon vaccines encode a replication machinery of an alpha virus that contains the target gene. So, new RNA vaccines multiply the transcript of the viral antigen several times for a long time and attained strong elicitation of innate and adaptive immune responses. Besides, similar to live attenuated vaccines, the dose sparing phenomenon is clearly traceable after injection of this type of RNA vaccines [124]. Another amazing feature of mRNA vaccine are the possibility of simultaneous containing of multiple mRNAs in a single dose of vaccine and applying as a prophylaxis because of its ability to induce immune responses similar to natural infection (Table 3). In this regard, the mRNA vaccine produced by Moderna Company, whose patent has been issued, was able to mix mRNA encoding whole S protein, as well as S1 and S2 subunits from MERS-CoV and SARS-CoV in the context of positive charge lipid nanoparticles. During the vaccination program, it was found that animals that received mRNA encoding the S2 subunit produced significantly fewer neutralizing antibodies than animals vaccinated with mRNA encoding the complete structure of the S protein. The use of mRNA encoding the full-length MERS-CoV S protein in white rabbits, in addition to a 90% reduction in viral load, produced a substantial neutralizing antibody response against MERS-CoV particles (WO2017070626). A previous patented study described that exploiting mRNA encoding ideally the S protein or S1 subunit, E and M, or N proteins would be effective in priming antigen-specific responses against MERS infection (WO2018115527). Similarly, intradermal injection of mRNA complex-entrapped in lipid capsules encoding the S protein of the MERS-CoV into mice induced specific antibody responses. Therefore, based on the used strategies and methods in the previously registered patents for mRNA vaccines, Modrena finally unveiled the first shipment of human mRNA vaccines against COVID-19 called mRNA-1273 in the last week of February 2020. The mRNA-1273 vaccine contains the mRNA encoding a prefusion and stable conformation of SARS-CoV2 S protein that was developed in collaboration with Modrena and National Institute of Allergy and Infectious Diseases (NIAID) and funded by global Coalition for Epidemic Preparedness Innovations (CEPI) partnership. BNT162 is the other anti-COVID-19 mRNA vaccine that four variants including a1, b1, b2 and c2 based on various combinations of mRNA formats in lipid nanoparticles has released and received obligatory approvals from German regulators for further studies [51, 121]. CVnCoV, is the other lipid nanoparticle captured non-modified mRNA COVID-19 vaccine candidate that encodes full-length spike protein. Following mice and hamsters’ immunization with CVnCoV, potent anti-spike neutralizing antibodies along with strong Th and cytotoxic T cell responses especially in mice models were induced. The lung tissue of vaccinated hamsters preserved incredibly after deliberate infection with the SARS-CoV2 pathogen. Also, suboptimal vaccination in hamsters not only abort viral replication, but also left no adverse effects and provided substantial safety [125]. Arcturus Therapeutics incorporation discloses an innovative COVID-19 vaccine (LUNAR®-COV19 (ARCT-021)) which obtain encouraging outcomes following single shot in lab animals. This replicon vaccine utilizes the STARR™ technology to elicit strong and protracted SARS-CoV2 spike protein expression. Mice vaccination with a single dose of ARCT-021 led to heavy neutralizing antibody responses, which gradually increased within two months after injection. Besides, robust anti-spike specific CD8+ T cell and Th1 responses were induced and human ACE2 transgenic mice were largely immunized against SARS-CoV2 challenge after ARCT-021 vaccination [126]. LNP-nCoVsaRNA is another self-amplifying RNA vaccine candidate against COVID-19 that was developed by Imperial College London university and has recently entered safety phase Ι clinical trials. This vaccine encodes the spike protein of the SARS-CoV2 and its intramuscular injection in mice provoke specific IgG antibody and Th1 responses dose-dependently [127]. Another positive point is that the design of this vaccine will be completed in 14 days [128]. Other LNP-encapsulated vaccine candidates, including ChulaCov19 and SARS-CoV-2 mRNA vaccine are evaluating immunogenicity, tolerability, and safety in early clinical trials [52].