COVID-19 Vaccines

Written by: Hector Fernandez
Edited by: Jina Zhou and Esther Melamed
9/3/2020

Currently there is a large number of vaccine candidates in the R&D landscape for coronavirus prevention. As of July 20, 2020, there are more than a hundred candidates seeking to reach the market with twenty-three of them approved for clinical trials (with other developers making plans to start trials later this year), according to the World Health Organization.  The majority of vaccine platforms intend to stimulate the production of antibodies against the viral spike (S) protein which is essential for uptake of the virus by epithelial cells via the human ACE2 receptor. The following article will provide an overview of the different types of vaccines currently in development as well as a brief summary of the more prominent vaccine candidates undergoing clinical trials. 

Types of COVID-19 Vaccine Candidates

The ongoing pandemic has spurred an explosion of candidate vaccines attempting to reach the market and gain approval for the first official COVID-19 vaccine. These range from more traditional vaccines, such as whole-pathogen vaccines, to more modern “new generation” technologies which incorporate a specific antigen or antigens from the virus. Table 1 gives an overview of the different vaccine types currently being considered for development.

Table 1 – Vaccine type overview.

Vaccine Type	Mechanism	Advantages	Disadvantages
Live-attenuated vaccines	Consists of live pathogens with reduced virulence that causes a mild infection which resembles the real infection inducing a strong immune response	Elicit a strong immune response Long-lasting protection Highly established product development and manufacturing process	Potential safety concerns due to higher reactogenicity compared to other types of vaccines Potential to infect immunocompromised people or reverse back to virulent strain
Inactivated vaccines	Thermally or chemically inactivated pathogens	Less reactogenicity Highly established product development and manufacturing process	Weaker immune response than live-attenuated vaccines Requires multiple dosages and adjuvants
Recombinant protein-based and vector-based vaccines	Incorporate a specific antigen or antigens from the pathogen only	Better safety profile Induce a precise immune response Weak immunogenicity	Epitope selection, antigen design, and vehicle development are not straightforward Not produced on large scale before
Trained immunity-based vaccine	Enhance innate immune response upon encounter with pathogen-associated molecular patterns	May boost the innate immunity against a wide range of infectious agents	Efficacy, and mechanisms not yet fully understood

Vaccine Delivery Systems in the Era of COVID-19

One of the noteworthy aspects of this race is the wide variety of technologies being developed to deliver the viral particle mimic (i.e. either the full S protein or the receptor binding domain (RBD) of the S protein) used to produce an effective immune response in the host. These range from previously used technologies, such as viral vector vaccines formerly developed for SARS-CoV, as well as more recently studied systems like the mRNA vaccines. Table 2 gives a brief overview of the current COVID-19 vaccine delivery system landscape.

Table 2 – Overview of COVID-19 vaccine delivery systems.

Vaccine Type	Delivery System	Example	Advantages	Disadvantages
Recombinant Protein	RBD or fusion of RBD that uses a carrier protein as antigen	NVX-CoV237	Most studied strategy Lower immunoreactivity than whole-pathogen vaccines	Typically, only induces specific humoral immune responses providing partial protection to viral infections Often require an adjuvant to increase immunogenicity
Viral Vector-Based	Antigen is cloned into a viral vector that lacks the ability to reproduce	ChAdOx1 nCoV-19	Viral vector mimics viral infection and can produce a strong immune response No adjuvant required	Some populations have existing antibodies against the vehicle virus, decreasing efficacy Poor thermostability
Bacterial Vector-Based	Uses non-pathogenic bacteria to deliver antigen such as a lactic acid bacteria (LAB)	bacTRL-Spike	Generally safe profile Low cost Can be lyophilized to provide better stability	Weak immunogenicity No previously approved products
Plasmid DNA	Uses a handheld electroporation device to deliver plasmid containing the genetic material to encode the antigen	INO-4800	Good safety profile Relatively straightforward manufacturing process ds-DNA molecules more stable than virus Can be freeze-dried for long-term storage	Low transfection efficacy, requiring transfection modalities like electroporation devices
Messenger RNA	Uses lipid nanoparticles (LNPs) to incorporate mRNA molecule to deliver to cells	mRNA-1273	all components can be produced via chemical synthesis Elimination of using live materials allows for quick product switching in manufacturing facilities negligible risk of host DNA integration is	mRNA molecules have low transfection efficacy, requires LNP for transport Thermostability issues

Vaccine Clinical Trials 

The following table provides an overview of some of the top contender vaccine candidates under clinical development (for a comprehensive list please visit: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ). 

Table 3 – Summary of vaccine candidates currently in clinical trials.

Vaccine Candidate	Characteristics	Developer	Status	NTC/Identifier
mRNA-1273	mRNA vaccine that encodes for a prefusion stabilized form of the spike (S) protein of the virus	Moderna	Phase III	NCT04283461
INO-4800	Optimized DNA plasmid that encodes for spike (S) protein	Inovio Pharmaceuticals	Phase I	NCT04336410
Ad5-nCoV	Adenovirus-based viral vector vaccine that expresses the spike (S) protein	CanSino Biologicals	Phase III	NCT04313127
Pathogen-specific aAPC	Artificial antigen presenting cells (aAPCs) modified to present selected viral proteins	Shenzhen Geno-Immune Medical Institute	Phase I	NCT04299724
LV-SMENP-DC	Uses lentiviral vector system to express viral proteins and immune modulatory genes to modify dendritic cells (DCs) and activate T cells	Shenzhen Geno-Immune Medical Institute	Phase I	NCT04276896
ChAdOx1	Adenovirus-based viral vector vaccine that expresses the spike (S) protein	University of Oxford	Phase II/III	NCT04324606
BNT162b2	mRNA vaccine that encodes for a prefusion stabilized form of the spike (S) protein of the virus	BioNTech/Pfizer	Phase II/III	2020-001038-36
CoronaVac	Inactivated, SARS-CoV-2 virus vaccine	Sinovac	Phase III	NCT04324606

mRNA-1273

• mRNA vaccine that encodes for a prefusion stabilized form of the Spike (S) protein (allows virus into cells)
• Phase I, open-label, trial enrolling 45 healthy adult volunteers ages 18 to 55 years over approximately 6 weeks.
  • Start Date: March 16, 2020.
  • Estimated study completion date: Pending
• Developed by Moderna, Inc.
• Moderna published Phase I results on July 14, 2020.  

INO-4800

• DNA vaccine (optimized DNA plasmid) which utilizes the CELLECTRA® electroporation platform to deliver the plasmid into cells.  
• Phase I, open-label, trial enrolling 40 healthy participants ages 18 to 50 years.
  • Start date- April 3, 2020
  • Estimated study completion date – November 2020
• Developed by Inovio Pharmaceuticals 

Ad5-nCoV

• First vaccine for COVID-19 in a Phase 1 Clinical Trial in China
• Uses CanSinoBIO’s adenovirus-based viral vector vaccine technology platform to express SARS-CoV-2 spike protein
• Phase I, open-label, trial enrolling 180 healthy participants ages 18 to 60 years.
  • Start date: March 16, 2020
  • Estimated study completion date: December 20, 2022
• Developed by CanSino Biologics Inc. 

LV-SMENP-DC

• Vaccine exploits COVID-19 engineered minigenes, which are delivered via a lentiviral vector system (NHP/TYF), to express viral proteins and immune modulatory genes. This technology hopes to modify dendritic cells (DCs) and therefore activate T cells to fight the virus.
• Phase I, open-label, trial enrolling 100 Laboratory (RT-PCR) confirmed Covid-19 infection participants ages 6 months to 80 years.
  • Start date: March 24, 2020
  • Estimated study completion date: December 31, 2024
• Developed by Shenzhen Geno-Immune Medical Institute 

Covid-19 aAPC Vaccine

• This vaccine works by applying a lentiviral vector system (NHP/TYF), which contains immune modulatory genes and viral minigenes, to artificial antigen presenting cells (aAPCs). The Covid-19/aAPCs are then inactivated for proliferation and subcutaneous injected at 0, 14 and 28 days (each injection approximately containing 5×106 cells).
• Phase I, open-label, trial enrolling 100 healthy and Covid-19-positive participants ages 6 months to 80 years.
  • Start date: February 15, 2020
  • Estimated study completion date: December 31, 2024
• Developed by Shenzhen Geno-Immune Medical Institute 

ChAdOx1

• Originally developed to target MERS, ChAdOx1 uses an attenuated adenovirus viral vector (which commonly causes infections in chimpanzees) that is engineered to produce the spike (S) protein of SARS-CoV-2
• Phase I/II single-blinded, randomized study enrolling 1112 healthy participants aged 18-55 years. 
  • Start date: April 23, 2020
  • Estimated study completion date: May 2021
• Developed by the University of Oxford. 

BNT162

• mRNA-based coronavirus vaccine encapsulated in Lipid Nanoparticles (LNPs).
• Phase I/II multi-site, 2-part, dose-escalation trial enrolling 196 healthy adult participants aged 18-55
  • Start date: April 20, 2020
  • Trials started in US on May 4, 2020
• Developed by BioNTech and Pfizer

CoronaVac

• Purified, inactivated, SARS-CoV-2 virus vaccine. This candidate showed a robust production of SARS-CoV-2-specific neutralizing antibodies in animal studies. 
• Phase I/II randomized, double-blinded, single-center, placebo-controlled clinical trial enrolling 744 (44 at phase I, 600 at phase II) healthy adults aged 18-59 years
  • Start date: April 16, 2020
  • Estimated study completion date: December 13, 2020
• Developed by Sinovac Research & Development Co., Ltd.
• The Sinovac, in conjunction with the Brazilian biotech company Butantan, were granted approval for a Phase III trial in July 3, 2020.

References

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