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    A review on COVID-19 mRNA vaccine candidates in clinical trials: design, target and formulation strategies

  • Saeideh Khorshid Sokhangouy,1,* Yalda Samsami,2
    1. Mashhad University of Medical Sciences
    2. Mashhad University of Medical Sciences


  • Introduction: Ongoing Coronavirus disease 2019(COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2(SARS-CoV-2) has impressively affected many dimensions of human lives and results in millions of infections and deaths worldwide. There is no recognized treatment for COVID-19 and Vaccination has been introduced as the last hope to stop the pandemic. Various vaccine platforms have been used for COVID-19 vaccine development. Among them, mRNA vaccines belong to Pfizer/BioNTech and Moderna companies demonstrated both high efficacy and safety and were the pioneers to receive FDA full approval. This transformative technology has unique advantages over other vaccine platforms. mRNA vaccines are Rapidly designed and produced through a simple manufacturing process. They can induce both potent humoral and cellular responses and importantly are safer than DNA vaccines. Of note, this platform is versatile to design novel variant-specific vaccines so is the best vaccine technology for emerging viruses such as SARS-CoV-2 and influenza. Importantly, recent improvements in the field of stability and delivery spot more light on this technology. These improvements include the efficient delivery of mRNA by lipid nanoparticles(LNPs) delivery system and, the utilization of modified nucleotides to enhance protein production and avoidance of excessive innate immune activation. There are also other COVID-19 mRNA vaccines in preclinical and clinical trials with promising results which are developed in order to respond to the current requirement for more efficient vaccines to control the pandemic. Approximately, most COVID-19 mRNA vaccines are used prefusion stabilized spike protein as the target antigen. Spike protein is placed on the virus envelope, composed of S1 and S2 subunits, and mediates the virus entry into the host cells through the interaction of receptor-binding domain(RBD) of S1 subunit with angiotensin-converting enzyme-2(ACE2) receptor on the host cell surface. Further proteolytic cleavage of spike protein into the S1 and S2 domains caused the virus envelop and cell membrane fusion and viral entry. Two proline substitutions in the spike protein(S-2P) stabilize it in the prefusion state which further enhances the stability and immunogenicity. Here, we comprehensively describe different COVID-19 mRNA vaccine candidates in clinical trials. We explain each vaccine design, target, and important results. Finally, we discuss the most important future prospects and describe some strategies to develop more efficient COVID-19 mRNA vaccines.
  • Methods: This current review has been done by searching for original articles of COVID-19 mRNA vaccines in clinical trials in PubMed, Web of Science, and Scopus databases.
  • Results: The recent approval of two mRNA vaccines, BNT162b2 and mRNA-1273, and their impressive success, encouraged scientists to develop more COVID-19 mRNA vaccine candidates with different designs and targets. Collectively 5 vaccine candidates are in clinical trials. Two candidates are based on self-amplifying mRNA. One candidate, named CVnCoV, showed 48% efficacy in the phase 3 clinical trial and failed to receive approval.
  • Conclusion: The concept of mRNA as a new therapeutic strategy was introduced in 1989. Then mRNA drugs rapidly developed to clinical trials. During the last decades, mRNA-based vaccines have demonstrated encouraging results against infectious disease and cancer. Notably, two mRNA vaccines encapsulated in lipid-nanoparticle (LNP), BNT162b2 and mRNA-1273, have demonstrated the most promising results in the prevention of COVID-19 infection. These vaccines have shown 95% efficacy and were the first mRNA vaccines to be licensed for emergency use. Also, there are more COVID-19 mRNA vaccine candidates which rapidly developed to clinical trials and showed promising results. Despite the remarkable success of these vaccines, there remain challenges that need to be addressed. For instance, a high dosage of mRNA used in these vaccines has led to enhance production costs and caused some side effects related to LNP components. Also, novel SARS-Cov-2 variants have emerged which can escape from previously induced immunity by vaccines. Therefore, some strategies need to employ in order to develop more effective mRNA vaccines with reduced doses and costs. One potential strategy is to improve the translational efficiency of mRNA by optimization of mRNA design, 5’capping method, and polyadenylation approach to reduce the effective dose necessity for immunogenicity as well as side effects and costs. Another strategy to compensate for the reduced efficacy of COVID-19 mRNA vaccines is to develop SARS-CoV-2 variant-specific vaccines by employing the variant spike sequence. Collectively, more researches need to perform in order to optimize mRNA vaccines and enhance their efficacy.
  • Keywords: COVID-19, mRNA vaccine, SARS-CoV-2, vaccination