mRNA vaccine
These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells.
[13][14] In 2023 the Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19.
[3][20] These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue[3] and led to the concept proposal of messenger RNA vaccines.
[24] The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice.
[29][30] Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported.
[29][31] Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008.
[36][37] The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field.
[36] DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology.
[42][43] The COVID-19 pandemic, and sequencing of the causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines.
[47] The goal of a vaccine is to stimulate the adaptive immune system to create antibodies that precisely target that particular pathogen.
[54] The mRNA fragments are translated in the cytoplasm and do not affect the body's genomic DNA, located separately in the cell nucleus.
It has a 5' cap, a 5'-untranslated region (UTR) and 3'-UTR, an open reading frame (ORF), which encodes the relevant antigen, and a 3'-poly(A) tail.
Enriching the sequence with guanine-cytosine content improves mRNA stability and half-life and, in turn, protein production.
[4] For a vaccine to be successful, sufficient mRNA must enter the host cell cytoplasm to stimulate production of the specific antigens.
[58] The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis, a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation.
[55] Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in the body, in vivo approaches have been investigated.
[20] They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection.
One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response.
In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions.
The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment.
Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions.
Typical RNA viruses used as vectors include retroviruses, lentiviruses, alphaviruses and rhabdoviruses, each of which can differ in structure and function.
[75] Clinical studies have utilized such viruses on a range of diseases in model animals such as mice, chicken and primates.
[80] They can also be manufactured faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks.
The mRNA is translated in the cytosol, so there is no need for the RNA to enter the cell nucleus, and the risk of being integrated into the host genome is averted.
[52] An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.
[84][85] Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient.
[88][89] In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions.
[4] The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick, and the person feeling as if they are as a result.
The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell.
