Since the emergence of SARS-CoV-2 in China [1], the resulting COVID-19 pandemic has presented a significant challenge to the global scientific community. The urgent need for a vaccine to decrease both the incidence and the impact of the disease remains apparent, with over 56 million cases diagnosed and more than 1.3 million deaths worldwide as of November 2020 [1]. Recent announcements from pharmaceutical companies Pfizer and Moderna regarding Phase III clinical trial results of their messenger RNA (mRNA) vaccine candidates (followed shortly by a similar announcement from AstraZeneca with respect to their more conventional vaccine candidate) have understandably received intense public attention. Reportedly demonstrating 95% [2] and 94.5% efficacy [3], respectively, with no major safety concerns, these novel mRNA therapeutics may become the first of their kind to gain approval for use in humans [4].
Unlike conventional vaccines, in which inactivated or attenuated pathogens are injected into patients to trigger antibody production and confer immunity, mRNA vaccines provide a template for cells to produce the specific antigen of the pathogen of interest [5]. Currently, there are two main types of RNA that have been studied for use in vaccines: non-replicating mRNA and in vivo self-replicating mRNA [5]. Non-replicating mRNA encodes the antigen and two flanking untranslated regions (UTRs), whereas self-replicating mRNA encodes the antigen and replication machinery, facilitating more abundant protein expression [5].
To produce an mRNA vaccine, mRNA is transcribed from the relevant DNA fragment in vitro using RNA polymerase [5]. The resulting product contains additional genetic components (an open reading frame, two flanking UTRs, a 5′ cap and a polyA tail) so that the template resembles fully processed, mature mRNA that would naturally occur in the cytoplasm of cells [5].
The mRNA vaccines are formulated with numerous in vitro and in vivo reagents that have been developed to prevent degradation and promote cellular uptake [5]. After administration to patients, the mRNA enters the cytoplasm of cells, where ribosomes subsequently translate the mRNA into the viral protein and synthesise multiple copies of the viral antigen, displaying them on the cell surface to trigger antibody production [6]. This exposure primes the immune system to respond more quickly and more aggressively if it encounters the same pathogen again [6].
Particularly in the context of a pandemic, the key advantage of mRNA vaccines is the acceleration of development and manufacturing timelines. After genetic sequencing of the required antigen, batches of mRNA can be generated within weeks using a cell-free and highly scalable process [7]. Although AstraZeneca has reported that their conventional vaccine, engineered from the common cold adenovirus and developed in a similar time frame to the Pfizer and Moderna mRNA vaccines, has an average efficacy of 70% [8], isolating, culturing and purifying pathogen samples is typically time-consuming and contributes to the delay in production of these vaccines compared with mRNA vaccines (which do not require these protocols).
Pfizer’s and Moderna’s mRNA vaccine candidates are undoubtedly promising in the battle against COVID-19, bringing hope to many in these difficult times. With the vaccine candidates proving to be effective and well tolerated in the populations studied, both companies are expected to seek emergency approval from the Food and Drug Administration and European Medicines Agency in the coming weeks. However, lack of long-term safety data, the logistics of international distribution and public misinformation are valid concerns that may hinder the success of what may be our greatest weapon in the ongoing fight against COVID-19.
References
1. GOV.UK. COVID-19: Epidemiology, virology and clinical features. Available at: https://www.gov.uk/government/publications/wuhan-novel-coronavirus-background-information/wuhan-novel-coronavirus-epidemiology-virology-and-clinical-features. Accessed November 2020.
2. Pfizer. Pfizer and BioNTech conclude phase 3 study of COVID-19 vaccine candidate, meeting all primary efficacy endpoints; November 2020. Available at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine. Accessed November 2020.
3. Moderna. Moderna’s COVID-19 vaccine candidate meets its primary efficacy endpoint in the first interim analysis of the phase 3 COVE study; November 2020. Available at: https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy. Accessed November 2020.
4. STAT. The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race. Available at: https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-the-covid-vaccine-race/. Accessed November 2020.
5. Pardi N, Hogan MJ, Porter FW et al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov 2018; 17 (4): 261–279.
6. PHG Foundation. RNA vaccines: An introduction. Available at: https://www.phgfoundation.org/briefing/rna-vaccines. Accessed November 2020.
7. Jackson NAC, Kester KE, Casimiro D et al. The promise of mRNA vaccines: A biotech and industrial perspective. NPJ Vaccines 2020; 5: 11.
8. AstraZeneca. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19; November 2020. Available at: https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html#!. Accessed November 2020.
Author: Emma Watterson, Associate Medical Writer, Porterhouse Medical
Group