The coronavirus disease 2019 (COVID-19) has spread worldwide and imposed a substantial burden on human health, the environment, and socioeconomic development, which has also accelerated the process of nucleic acid vaccine development and licensure. Nucleic acid vaccines are viral genetic sequence-based vaccines and third-generation vaccines after whole virus vaccines and recombinant subunit vaccines, including DNA vaccines and RNA vaccines.
Coronaviruses (CoVs) are widespread in nature and can cause multisystem disorders in humans 
, including the respiratory and alimentary tract, nervous system, etc., and lead to immense financial loss at the same time 
. To date, CoV infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have resulted in three global pandemics 
. Due to its greater ability to recognize receptors 
, SARS-CoV-2 spreads more efficiently from person to person 
. Currently, drug development is side-by-side with vaccine upgrading. Vaccination is the most effective strategy for preventing and controlling infectious diseases 
. Multiple types of SARS-CoV-2 vaccines have been developed at the same time 
, and some of them have successively been granted emergency use authorization by the World Health Organization (WHO), mainly including inactivated vaccines 
, adenovirus-vectored vaccines 
, and nucleic acid vaccines 
. Due to well-established technology, vaccination with inactivated vaccines is the primary method used during our epidemic prevention and control mechanisms. However, vaccination with inactivated vaccines, in most cases, result in the generation of humoral, but not cell-mediated, immune responses. With the deepening research of virology and the gradual maturation of vaccine technology, substantial progress has been made in the development and application of nucleic acid vaccines, which, as an emerging platform, have become a hotspot in the vaccine research and development field.
Nucleic acid vaccines, as an emerging concept, were established in the early 1990s 
and include DNA vaccines and RNA vaccines, which were also third-generation vaccines after whole virus vaccines and recombinant subunit vaccines. After introducing foreign target genes, they use the protein synthesis systems of host cells to express target proteins and then induce immune responses. Before the outbreak of coronavirus disease 2019 (COVID-19), nucleic acid vaccines were not yet available for human use on the market. The unprecedented pandemic scenario has accelerated the vaccine development and licensure process.
2. The Research and Development Process of Nucleic Acid Vaccines
The research and development procedure of nucleic acid vaccines involves two main phases: early design stage and clinical experiment stage. More details are shown in Figure 1
. The early design stage generally consists of searching for immunogens, designing vaccine structures, and determining toxicological effects and immune effects in animal models. The clinical experiments targeting primarily practical application mainly aim to provide definitive evidence for the safety and efficacy of vaccines. According to regulations of special approval processes, on the premise of guaranteeing the security and stability of COVID-19 vaccines, it is admissible to reduce certain approval processes accordingly 
. Additionally, the vaccine life cycle includes production, supply, available on the market, and post-marketing research in the real world. Currently, the ZyCoV-D vaccine developed by Cadila in Ahmedabad, Gujarat, India is the first DNA vaccine for people to be approved anywhere in the world 
. INO-4800, developed by Inovio (the leading global development corporation of DNA vaccines), is the first DNA vaccine to advance to clinical trials and is currently undergoing phase three clinical trials, having the prospect of being commercially available within one year. BioNTech/Pfizer and Moderna are two leading research teams for COVID-19 RNA vaccines. BNT162b2 from BioNTech/Pfizer and mRNA 1273 from Moderna were granted emergency use authorization by the WHO on 14 January 2021 and on 3 February 2021, respectively. An illustration of the current COVID-19 nucleic acid vaccines is presented in Table 1
Figure 1. Illustration of the research and development process for nucleic acid vaccines. The procedure involves an early design stage, clinical trial stage, review and approval stage, and post-market surveillance. The early design stage generally consists of searching for immunogens, designing vaccine structures, and determining toxicological effects and immune effects in animal models. The clinical trials mainly include phases Ⅰ–Ⅲ, targeting primarily practical applications to provide definitive evidence for the safety and efficacy of vaccines.