Rochapon Wacharotayankun, Ph.D., R.Ph.
Consultant, National Vaccine Institute of Thailand

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and Immune Response
It has been more than a year that the world is in the midst of COVID-19 pandemic caused by the novel severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). As of 18 March 2021, there are 120,667,101 confirmed cases of COVID-19, including 2,670,274 deaths (WHO), leading to widespread social and economic disruption. As a result of unprecedented worldwide efforts to develop countermeasures, many vaccines are being developed and some have been successfully approved for emergency use. A total of 326,858,656 vaccine doses have been administered. Currently, approximately 45,000 (0.1%) Thai people have been vaccinated comparing with global vaccination rate of 3% worldwide. This shows inequity of vaccine distribution to the low and middle incoming countries.



Figure 1.SARS-CoV-2 Virus and Immune Response
SARS-CoV-2 is a member of the Coronaviridae family, which comprises many virulent strains that infect humans and animals, including SARS-CoV and MERS-CoV. They cause mild to lethal respiratory tract infections in humans and birds. It is believed that the SARS-CoV-2 virus has zoonotic origins and close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus. SARS-CoV-2 is a positive-sense single-stranded RNA virus; each SARS-CoV-2 virion is 50–200 nanometres in diameter. Like other coronaviruses, SARS-CoV-2 has four structural proteins, i.e., the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins; the N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope. The spike protein comprises S1 and S2 subunits, is responsible for entry to the host cell by attachment and fusion to the Angiotensin converting enzyme 2 (ACE2) receptor; its S1 subunit, specifically the Receptor binding domain (RBD) catalyzes attachment and the S2 subunit fusion. Natural infection of the SARS-CoV-2 virus generates both mucosal and systemic immunity. The inflammatory response plays a crucial role in the clinical manifestations of COVID-19. Post SARS-CoV-2 entry, host factors trigger an immune response against the virus, which, if uncontrolled, may result in pulmonary tissue damage, functional impairment, and reduced lung capacity. Elderly patients and patients with non-communicable diseases are more vulnerable to SARS-CoV-2 virus infection.

COVID-19 Vaccine Development
As of 16 March 2021, there are 82 vaccines in clinical development and 182 vaccines in pre-clinical stage. Among 82 vaccines in clinical trial stage, 5 vaccines have either emergency use approval or conditional approval.
Among all candidate vaccines in clinical phase, 33% are subunit vaccines, 15% are non-replicating viral vector vaccines, 13 % are for DNA vaccines and another 13% are Inactivated vaccines.



Figure 2. COVID-19 Landscape of novel coronavirus candidate vaccine development as of 15 March 2021.





Figure 3. COVID-19 Vaccine Platform Technologies
Currently, there are several platform technologies used for COVID-19 vaccine development. Among these 10 approaches, there are 3 front runner platforms which are in Clinical trial phase 3 and have been granted emergency use/ conditional approval in many countries, i.e., mRNA, Non-replicate Viral vector (Adenoviral vector) and Inactivated vaccine. Candidate vaccines produced by other platform technologies such as Subunit vaccines and DNA vaccines are also in Clinical trials phase 3.
It is interesting that Subunit vaccines are the highest number of candidate vaccines in clinical trials but none have been approved for emergency use, so far.

COVID-19 Vaccine R&D in Thailand
Thailand has strategic policies to ensure that at least more than 50% of Thai population can get access to COVID-19 vaccines one of which is to support a Thai biotech, Siam Bioscience Co., Ltd. to contract manufacture the Oxford/AstraZeneca (ChAdOx1-S - AZD1222) vaccine which will contribute approximately 20% of Thai people. A number of doses of COVID-19 vaccines will be imported from various manufacturers.
Apart from that, Thailand is supporting several vaccine research and development projects in the country in order to be self-sufficient and also contribute to the scientific community for the COVID-19 vaccine development as shown in Table 1.

Platform	Name	Company / Organization	Description	Status
Inactivated virus	Inactivated NDV LaSota-based COVID-19 vaccine (NDV-HXP-S)	Government Pharmaceutical Organization (GPO; Thailand) / Dynavax / PATH	Egg-based, inactivated, whole chimeric Newcastle Disease Virus (NDV)- Lasota expressing membrane-anchored pre-fusion-stabilized trimeric SARS-CoV-2 S protein (Hexapro) + CpG 1018	Clinical phase 1 (March 2021)
mRNA	ChulaCov19	Chula Vaccine Research Center	Lipid nanoparticles encapsulated, modified mRNA encoding prefusion wild-type (WT) full-length S-spike protein.	-Preclinical completed -To enter clinical phase by April-May 2021.
DNA	Covigen	BioNet-Asia	Purified plasmid DNA vaccine encoding SARS-CoV-2 spike protein subunit 1 (S1) in pVAX1 vector using Pharmajet (Stratis™ and Tropis™)	Preclinical
Plant-based protein subunit vaccine		Baiya Phytopharm	Plant-based receptor-binding domain (RBD) of SARS-CoV-2 fused with Fc fragment of human IgG1 expressed in Nicotiana benthamiana using Agrobacterium vector + Adjuvant	Preclinical
VLP	Not available	Mahidol University/ The Government Pharmaceutical Organization (GPO)/Siriraj Hospital	VLP -Spike (S), Matrix/membrane (M) and Envelope (E) of SARS-CoV-2 expressed in Sf21 cell line + Th1 bias Adjuvant	R&D (Non-regulated animal study)
Protein subunit	Not available	Mahidol University	Recombinant HexaPro S protein expressed in HEK293 cells + aluminium hydroxide	R&D (Non-regulated animal study)
Live attenuated vaccine	scIAV-NA-RBM / scIAVRBD-HA	National Science and Technology Development Agency : NSTDA Development Agency : NSTDA	Single-cycle influenza A virus (scIAV)-based vaccines for intranasal administration	R&D
VLP	Not available	National Science and Technology Development Agency : NSTDA	Virus-like particle (VLP)-based vaccines (S protein or RBD)	R&D
Non-replicate Viral vector	Ad-S	National Science and Technology Development Agency : NSTDA	Human Adenovirus 5 based– S protein	R&D

Table 1. Current COVID-19 vaccine research and development projects in Thailand