**4. Vaccine development**

To monitor the global SARS-CoV-2 pandemic, a vaccine development becomes mandatory. The development of a vaccine that provides durable protective immunity will be the most effective therapy for controlling possible epidemics of this virus. The ideal vaccine should be safe, effective, durable, and accessible to a large population. Moreover, the virus genome has the ability to mutate so that it is necessary to develop a safe and pangenotypic vaccine to be effective toward any SARS-CoV-2 variants.

The majority of vaccine approaches have the ability to generate neutralizing antibodies against specific proteins, particularly the spike protein. Some adjuvant components can be added to the vaccine to stimulate the immunity and reduce the amount of antigen required for each vaccine dose. As of August 2022, 222 vaccine candidates

were included in the international clinical phase, and 774 vaccines were included in the preclinical phase [29]. The vaccine platforms include viral vector nonreplicating vaccines, protein subunits, DNA-based vaccines, RNA-based vaccines, viral vector replicating vaccines, virus such as particle, live attenuated virus, and bacterial antigen spore expression vector (**Figure 2**) [31, 32].

Several years of research are needed to develop a safe vaccine that can be used in clinical trials. Vaccine evaluation is usually performed in phases after development [33]. Preclinical testing on cell lines and animal models is required in Phase I, followed by testing on a small number of people to affirm immune system stimulation [33]. Phase II involves examining hundreds of people, including children and the elderly, to ensure safety in a new cohort [34]. Finally, thousands of people will be tested in the Phase III trial. During this phases, scientists administer vaccines to volunteers and monitor how many of the placebo and vaccine groups become infected. Typically, these trials are used to monitor if the vaccine provides protection against the virus and detect the absence/presence of adverse effects. Phase III trials are sufficiently large to report efficacy rates, as well as rare side effects.

Of all the vaccines in clinical trials with the SARS-CoV-2 variant, the RNA vaccine appears to be more effective than other vaccines because it requires the development of a large number of vaccines with a limited budget. Although clinical trials are harmless, immune responses elicited by antigens stimulated by RNA vaccines are fewer than those found in animal models [35, 36]. Similar to RNA ‐ based vaccines, DNA-based vaccines are easier and cheaper to provide better safety, efficacy, and long-term immune response. Nevertheless, it has not been approved for human use because it has not elicited a strong enough immune response to be safe. Vaccines based on highly immunogenic vectors, on the other hand, have been shown to induce effective immune responses.

The vaccines that have been registered in phase III clinical trial include vector vaccines (University of Oxford/AstraZeneca, Janssen Pharmaceutical Companies and Gamaleya National Research Centre), mRNA-based vaccines (Pharma/Pfizer and Moderna/National Institute of Allergy and Infectious Diseases), inactivated vaccines (Beijing Institute of Biological Products, Wuhan Institute of Biological Products, and adjuvant recombinant protein nanoparticles (Novavax) [37].

#### **Figure 2.**

*Illustrates the all the types of approaches for the vaccine development [30].*
