Meet the mRNA vaccine rookies aiming to take down COVID-19

Meet the mRNA vaccine rookies aiming to take down COVID-19

Updated: December 4, 2020 While therapeutic agents to treat COVID-19 in those already infected are being actively investigated, and will likely save many lives, there is a growing belief that a safe and effective vaccine is the only long-term solution. Recently, a study published in Cell revealed that asymptomatic and mild cases of COVID-19 result

Updated: December 4, 2020

While therapeutic agents to treat COVID-19 in those already infected are being actively investigated, and will likely save many lives, there is a growing belief that a safe and effective vaccine is the only long-term solution. Recently, a study published in Cell revealed that asymptomatic and mild cases of COVID-19 result in a robust T cell-mediated immune response, even when antibodies specific to the virus cannot be detected. This finding supports the theory that widespread vaccination could be effective in rapidly mitigating spread and eventually ending this pandemic.

As of December 2, 2020, the collaborative efforts of governments, universities and commercial R&D organizations have yielded 214 candidate vaccines for COVID-19, of which 51 are in clinical evaluation and 13 have reached Phase 3 clinical trials. Of these leading candidates, two are mRNA vaccines, which represent the cutting-edge technology in vaccine platforms and offer  many potential advantages over conventional vaccines.


Watch this video to see how an mRNA vaccine uses our bodies’ cells to generate immunity to COVID-19. 

 


What is an mRNA vaccine? 

mRNA (messenger RNA) is like a blueprint that carries the information cells use to produce different proteins. Inside human cells, two major steps are required to manufacture proteins based on the genetic information in the DNA. First, in the nucleus, the information encoded in DNA is transferred to mRNA via a process called transcription. Then, the mRNA moves from the nucleus to the cytoplasm where ribosomes translate the mRNA into protein, which performs functions of our cells and tissues.

In contrast to conventional vaccines, which directly introduce antigenic proteins that stimulate an immune response in the host, mRNA vaccines introduce mRNA encoding a disease-specific antigen and leverage the host cells’ protein synthesis machinery to produce antigens that elicit the immune response. The production of these foreign antigens within the body prepares the immune system to recognize and memorize this viral antigen so it is ready to fight off future infections caused by virus with the same antigen.

mRNA vaccines trigger the body’s normal infection-fighting process

During a viral infection, immune cells, known as T cells and B cells, work hand-in-hand to induce both cell-mediated immunity and antibody-mediated immunity, respectively. In cell-mediated immunity, cytotoxic T cells kill the virus-infected cells, whereas in antibody-mediated immunity, antibodies neutralize the virus itself. mRNA vaccines closely albeit harmlessly mimic the virus’ ability to trigger the body’s immune responses to infection and elicit both types of immunity. Figure 1 illustrates the additional mechanism by which mRNA vaccines induce immunity

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Figure 1. Mechanism of action of mRNA vaccines

Upon vaccination, the mRNA vaccine encoding the viral spike protein packaged in a lipid nanoparticle enters the cell. There, it is translated in the ribosome into protein. This protein is either broken into smaller pieces (peptides) by the proteasome or transported via the Golgi apparatus to the outside of the cell. The smaller pieces remaining in the cell are then presented as a complex with an MHC (major histocompatibility complex) class I protein on the cell surface. This complex is recognized by CD8+ T cells generating cell-mediated immunity (left side of Figure 1). On the other hand, the spike proteins outside the cell can be taken up by different immune cells and broken into pieces in the endosome. These pieces are presented on the cell surface as a complex with an MHC class II protein, which is recognized by CD4+ T cells facilitating B cells to make antigen-specific antibodies (right side of Figure 1).

The path to ending a pandemic

Historically, vaccine development has been a long, complex and costly process that typically takes several years or even decades. However, tackling a highly infectious emerging virus like SARS-CoV-2 requires rapid development and large-scale deployment of a vaccine. mRNA offers a number of advantages in this situation. In addition to the increased specificity and efficacy resulting from induction of both B- and T-cell immune responses discussed above, the fact that mRNA can be produced in large quantities in a cell‐free environment by in vitro transcription (IVT) allows for faster development, a simplified production process and more cost-effective manufacturing.

Since the outbreak of COVID-19, there has been a great leap in mRNA vaccine development. Remarkably, Moderna took just two months to go from taking the full sequence of SARS-CoV-2 to designing a COVID-19 mRNA vaccine for clinical trials. In July, the company confirmed its safety and protective immune response found in a Phase 1 trial. Pfizer and BioNTech, through a collaborative effort, have also shown positive results for their mRNA vaccines. In August, they reported safety and immunogenicity data in a Phase 1 trial, which allowed the BNT162b2 candidate vaccine to enter into a Phase 2/3 trial. Pfizer announced that the companies could seek approval as early as October 2020, if a large study is successful. These and other mRNA candidate vaccines in human trials are listed in Table 1. All the COVID-19 mRNA vaccines produced so far encode the spike (S) protein of SARS-CoV-2 as the antigen.

As of November 30, 2020, both BioNTech/Pfizer and Moderna have applied for the emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for their mRNA vaccines after obtaining excellent results in terms of efficacy (95% and 94.1%, respectively) and safety from the Phase 3 trials. Furthermore, Moderna’s vaccine indicated 100% efficacy against severe COVID-19. On December 2, 2020, BNT162b2 vaccine received the first authorization in the UK and both mRNA vaccines are expected to obtain the EUA from the FDA in December.

Table 1. mRNA vaccines for COVID-19 in clinical development (updated Nov. 30, 2020)

Candidate vaccine

Candidate vaccine type

Developer/
Manufacturer

Current regulatory status (Trial ID

mRNA-1273

Lipid nanoparticle (LNP)-

encapsulated RNA

Moderna/NIAID

Phase 3 (NCT04470427)

BNT162b2

3 LNP-mRNAs

BioNTech/Fosun Pharma/Pfizer

Phase 3 (NCT04368728)

CVnCoV

mRNA

CureVac AG

Phase 2 (NCT04515147)

LNP-nCoVsaRNA

Self-amplifying RNA vaccine

Imperial College London/Morningside Ventures

Phase 1 (ISRCTN17072692)

ARCT-021

Self-replicating RNA and nanoparticle delivery system

Arcturus Therapeutics/Duke-NUS Medical School 

hase 1/2 (NCT04480957)

ARCoV

mRNA

Academy of Military Medical Sciences, Suzhou Abogen Biosciences and Walvax Biotechnology

Phase 1 (ChiCTR2000034112; ChiCTR2000039112)

In addition to development speed, the mechanism of action of mRNA vaccines in the body also provides a number of safety advantages. Although mRNA vaccines carry genetic information encoding the viral antigen, they do not integrate into the host cell genome or interact with DNA and therefore impose no mutational risk to the host. Also, there is no formation of viral particles with mRNA vaccines. As such, an mRNA vaccine itself would not induce the disease it prevents. In addition, the antigen expression after mRNA vaccination is transient, limiting its persistence in the body. 

However, two major challenges related to the immunogenicity and stability of mRNA vaccines have to be overcome to make them a viable clinical alternative to conventional vaccines. First, the mRNA strand in the vaccine might cause an unintended immune reaction. To minimize this, the mRNA vaccine sequences are optimized to mimic those produced by mammalian cells. Second, free mRNA breaks down quickly in the body, thereby attenuating any desired effect. To circumvent this, the mRNA has been incorporated into a fatty capsule (called a lipid nanoparticle) to improve stability and allow it to more easily get into cells. These advancements have enabled the broader use of mRNA vaccines.

It is yet unknown which COVID-19 vaccine candidate will make it to market first and which vaccine approach will be most effective against the virus in the long run. However, clinical trial evidence to date suggests that mRNA vaccines have high potential to be a fast, safe and efficient new platform. Though hopefully the COVID-19 pandemic will be behind us sooner rather than later, vaccine technology is one of many fields that will reap benefits from COVID-accelerated innovations well beyond the pandemic.

As part of the global scientific community, CAS has committed to leveraging all of our assets and capabilities to support the fight against COVID-19. Explore the additional CAS COVID-19 resources including scientific insights, open access compounds and SAR datasets, and special reports.

 

Soruce: https://support-cas-org.ezproxy.uindy.edu/blog/covid-mrna-vaccine

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