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].