- Synthetic DNAs (INO-4800) are much easier to design and amplify
    - They are resistant to nucleases
- INOVIO was used to create the MERS-CoV vaccine
- Induction of INO-4800 to African green monkey fibroblast (COS-7) and human kidney (HEK-293T) cell lines both showed substantial levels of antibodies in serum
    - Capable of activating cellular and humeral responses within several days after 
       immunization
- Spike protein expression was measured by Western blot to be consistently high 
   and was further confirmed qualitatively through immunofluorescence staining.
- INO-4800 exhibits competitive inhibition against ACE2 receptors and was detected in the lungs that halted Lower Respiratory Disease 

Inovio INO-4800

INO-4800 targets the MERS coronavirus Spike protein. The nucleic acid vaccine by attaching to the receptor-binding site and neutralizing the epitopes. The vaccine has initiated a humoral and T-cell response as well as a spike in antibodies which function via competitive inhibition of the ACE2 receptor which the novel coronavirus also binds to. NCT04336410 is optimized through electroporation.

Smith College

University of California, Santa Cruz

Carnegie Mellon University

- mRNA-1273 (NCT04405076) Vaccine 
- BNT162b1/BNT162b2/BNT162b3 (NCT04368728) Vaccines
- INO-4800 (NCT04336410) Vaccine
- NCT04334980 Vaccine

Nucleic Acid Vaccines in Clinical Trial for COVID-19

"Electroporation, or electropermeabilization, is a microbiology technique in which an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, or DNA to be introduced into the cell."

Electroporation 

1. mRNA-1273 (moderna)
2. BNT162b2 (pfizer and biontech)
3. adenovirus type-5 (Ad5)-vectored COVID-19 vaccine (Cansino)
4. rAd26-S and rAd5-S (gamaleya)
5. Ad26.COV2.S (johnson & johnson) 
6. ChAdOx1 (Astrazeneca and Oxford)
7. NVX-CoV2373 (novavax)
8. Inactivated COVID-19 Vaccine (Wuhan Institute of Biological Products)
9. BBIBP-CorV Vaccine (Sinopharm)
10. Sinovac
11. INO-4800 (NCT04336410) by Inovio Pharmaceuticals
12. Anhui Zhifei Longcom and the Chinese Academy of Medical Sciences Vaccine
13. BBV152 (Covaxin)

Phase 3 Vaccine Candidates

- NVX-CoV2373 from Novavax Inc
- Anhui Zhifei Longcom / Chinese Academy Vaccine
- CoVLP from Medicago
- rAd26-S and rAd5-S (Sputnik V) from the Gamaleya Center 
- Ad26.COV2.S from Johnson & Johnson
- Ad5-nCoV from CanSino Biologics
- ChAdOx1 nCoV-19 from The University of Oxford
- mRNA-1273 from ModernaTX
- BNT162b2 from Pfizer and BioNTech
- Bacillus Calmette-Guerin (BCG) Vaccine from Murdoch Institute in Australia
- Vaccine from Wuhan Institute of Biological Products Vaccine
- CoronaVac from Sinovac Biotech Ltd
- BBIBP-CorV from Beijing Institute of Biological Products
- BBV152 from Covaxin



Vaccine Candidates of Interest (Lit Review)

Smith, T.R.F., Patel, A., Ramos, S. et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 11, 2601 (2020). doi: 10.1038/s41467-020-16505-0

https://doi.org/10.1038/s41467-020-16505-0

Immunogenicity of a DNA vaccine candidate for COVID-19

Allam, M., Cai, S., Ganesh, S., Venkatesan, M., Doodhwala, S., Song, Z., . . . Coskun, A. F. (2020). COVID-19 Diagnostics, Tools, and Prevention. Diagnostics, 10(6), 409. doi:10.3390/diagnostics10060409

https://www.mdpi.com/2075-4418/10/6/409

COVID-19 Diagnostics, Tools, and Prevention

Shin, M.D., Shukla, S., Chung, Y.H. et al. COVID-19 vaccine development and a potential nanomaterial path forward. Nat. Nanotechnol. 15, 646–655 (2020). doi: 10.1038/s41565-020-0737-y

https://doi.org/10.1038/s41565-020-0737-y

COVID-19 vaccine development and a potential
nanomaterial path forward

- mRNA-1273 is capable of triggering the adaptive immune response. This mRNA essentially codes for the viral spike (S) glycoprotein that is involved in receptor recognition with ACE2 receptors in host cells.
- Uses lipid nanoparticle dispersion that contains mRNA encoding  the stabilized prefusion SARS-CoV-2 spike protein 
- Pre-clinical trials: Rhesus macaque - administration of either 10 or 100 micrograms of the mRNA-1273 showed successful induction of type 1 helper T-cells (Th1)
- In phase 2 of clinical trials and planning on phase 3 later July.
-Supports a two dose (second administration) method of vaccination.

mRNA-1273 COVID-19 Vaccine by ModernaTX, Inc. 

- Lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccines that encode trimerized SARS-CoV-2 spike glycoprotein RBD.
- Currently in Phase 1/2 and testing 3 variations of the vaccines 
- Preliminary report on BNT162b1 available for phase 1/2

BNT162b1/BNT162b2/BNT162b3 Vaccines for COVID-19 by BioNTech/Fosun Pharma/Pfizer

INO-4800 (NCT04336410) by Inovio Pharmaceuticals

This "bacTRL-Spike oral DNA vaccine encoding S of SARS-CoV-2" is under Phase 1 trial.

NCT04334980 by Symvivo

Aimed to further assess the immunogencity and safety of Ad5-vectored COVID-19 vaccine in a larger population with only the 5 x 10^10 and 1 x 10^11 viral particles doses after the first-in-human phase 1 trial with CanSino Biologics (Tianjin, China) suggested high-dose vaccine was associated with a higher risk of severe adverse effects. 
- methods
- results
- discussions
- limitations and future work

Study on immunogenicity and safety of Ad5-vectored COVID-19 vaccine in larger population

mRNA-1273 is a candidate vaccine proposed by Moderna. The candidate vaccine is a lipid nanoparticle that contains an encapsulated, nucleoside-modified messenger RNA (mRNA). The mRNA codes for the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation, or the structure it has before it infects a cell. The S glycoprotein is a primary vaccine target as it controls host cell attachment and is needed for viral entry.

mRNA-1273 Vaccine against SARS-CoV-2 Overview

- Ad26.COV2.S is a vaccine candidate designed by Johnson & Johnson.
- It utilizes a non-replicating adenovirus 26 as a vector expressing the stabilized pre-fusion SARS-CoV-2 spike protein.
- It entered Phase 3 clinical testing in late September, becoming the fourth large-scale vaccine in phase 3 in the United States.

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From our Literary Review:
Johnson & Johnson vaccine candidate is phase 1/2a randomized, double blinded, placebo-controlled clinical study. The purpose of the study was to assess the safety, reactogenicity and immunogenicity of the Ad26.COV2.S. Ad26.COV2.S is a non-replicating adenovirus. The safety and immunogenicity data collected after only a single dose are supportive for further clinical development of Ad26.COV2.S.It is a 26 based vector aiming to express the spike protein of SARS-CoV-2. 


Ad26.COV2.S (Johnson& Johnson) Vaccine Overview

- ChAdOx1  are a desirable platform of vaccine because they are immunogenic in older adults and can be manufactured at large scale
- Vaccines made by combining adenoviral vectors, DNA, and poxviral vectors have been used in an attempt to improve immunogenicity--Emergence of antivector immunity inhibits the potency of a second dose, so homologous adenoviral regimens are typically avoided
- "The ChAdOx1 nCoV-19 vaccine (AZD1222) consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the full-length structural surface glycoprotein (spike protein) of SARS-CoV-2, with a tissue plasminogen activator leader sequence. ChAdOx1 nCoV-19 expresses a codon-optimised coding sequence for the spike  protein (GenBank accession number MN908947)."

ChAdOx1 nCoV-19 vaccine by The University of Oxford

- NVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimetric full-length SARS-CoV2 spike glycoproteins and Matrix M1 adjuvant
- Novavax identified this as its candidate with high immunogenicity and high levels of neutralizing antibodies
- September 24, 2020: Phase 3 clinical trials began in the UK and immunize 10,000 people in the next 4-6 weeks
- January 21, 2021: 22,000 volunteers enrolled worldwide

NVX-CoV2373 (Novavax) Vaccine Overview

The study aimed to investigate the safety and immunogenicity of an inactivated whole virus vaccine agains SARS-CoV-2. The results of Phase I and Phase II trials suggest that minimal adverse reactions were observed and that a multiple dose approach is needed. Non-human primate trials have been conducted, but large scale clinical trials in humans are needed to understand the efficacy and the potential for long-term adverse reactions.
- Methods
- Results
- Discussion

Inactivated Whole Virus vaccine by Wuhan Institute of Biological Products

This paper summarized the phase 1 and phase 2 trials of an inactivated vaccine against SAR-CoV-2. The safety and immunogenicity of the vaccine were assessed, including the adverse reactions and long term effects of the vaccine.

- Methods
- Results
- Discussion

BBIBP-CorV Vaccine (Sinopharm)

- Sinovac Vaccine is also known as CoronaVac SARS-CoV-2 Vaccine
- this is an inactivated pathogen it differs from how the other rival vaccine candidates are made using either DNA or RNA
- virus is grown in cultures and then inactivated it
- typically takes longer than other vaccines to develop

- Introduction 
- Methods
- Results
- Conclusion

 Sinovac Vaccine

From the Literary Review:

The plant based vaccine, CoVLP, uses trimeric spike glycoproteins from Nicotiana benthamiana to mimic the size and shape of SARS-CoV-2 (Ward et al., 2020). Medicago has had previous success utilizing other plant-based vaccines for the Influenza virus and H1N1, so the company decided to develop a VLP vaccine against SARS-CoV-2 as well (Medicago Begins Phase I Clinical Trials for Its COVID-19 Vaccine Candidate, n.d.). A randomized, partially-blinded, prime-boost, 21 days apart, dose escalation phase 1 study determined that the vaccine was well-tolerated and effective when used with adjuvants. Medicago has been approved by the government of Canada to initiate a phase 2/3 trial, which began on November 12, 2020. At the time of writing, CoVLP  is the only plant-based vaccine in phase 3 trials, offering diversity to the pool of vaccine candidates. This added diversity can allow for alternative prophylactic treatment options for those at risk for adverse reactions to other COVID-19 vaccines (Ward et al., 2020).
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CoVLP (Medicago) 

- Background
- Methods
- Results
- Conclusion

CoVLP Phase 1 Trial

- The Anhui Zhifei Longcom vaccine is a recombinant subunit vaccine
- June 19, 2020: approved for phase one clinical trials
- October 22, 2020: complete phase two clinical trials
- Entered Phase 3 clinical trials on November 20, 2020

Anhui Zhifei Longcom and the Chinese Academy of Medical Sciences Vaccine

- BBV152 is an inactivated SARS-CoV-2 vaccine in rhesus macaques. Both Phase 1 and Phase 2 were launched in India. The sponsor is Bharat Biotech International Limited and collaborator is Indian Council of Medical Research.
- Study Description
- Study Design
- Arms and Interventions
- Outcome Measures

BBV152 (Covaxin)

From our Literary Review:

With the aid of the Ministry of Health of the Russian Federation, russian researchers developed a vaccine composed of two distinct adenovirus vector components: recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5), each of which had been previously tested separately in clinical trials at Johnson and Johnson (USA) and at the CanSino Biological/Beijing Institute of Biotechnology (China), respectively.  The rAd26/rAd5 vaccine was developed and tested in healthy participants in phase 2 clinical trials after confirming the safety of the two individual vector components in phase 1. They ultimately found  that this heterologous vaccine is safe and immunogenic in healthy adults, but that further investigation is still needed to understand its effectiveness.

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Study on safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19

Investigates the safety and immunogenicity of a heterologous COVID-19 vaccine with two vector components: recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5), both of which carry the gene for the SARS-CoV-2 spike glycoprotein S.  This vaccine was developed in two formulations, frozen and lyophilized, and tested in healthy participants after confirming the safety of the two individual vector components in phase 1.  They ultimately find that this heterologous vaccine is safe and immunogenic in healthy adults, but that further investigation is still needed to understand its effectiveness.

- Methods

- Results

- Discussion
  
       
       

rAd26 and rAd5 vector-based Vaccine


Description from Literary Review:

NVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimetric full-length SARS-CoV2 spike glycoproteins and Matrix M1 adjuvant. A randomized, placebo-control, phase 1-2 trial was conducted on 131 healthy adults.  It has high immunogenicity and high levels of neutralizing antibodies. On September 24, 2020, phase 3 clinical trials began and immunized 10,000 people in the next 4-6 weeks. This took place at the Nucleus Network in Herston, Queensland and Melbourne, Victoria.
This vaccine candidate is a recombinant nanoparticle vaccine constructed from full-length wild-type SARS-CoV-2 spike glycoprotein. It includes Matrix M1 Which is a saponin based adjuvant made by Novavax. The rSARS-CoV-2 and Matrix M1 parts were mixed just before use. This vaccine is favorable because it can be stored between 2°C and 8°C, allowing for easy preservation and, therefore, distribution (Novavax Initiates Phase 3 Efficacy Trial of COVID-19 Vaccine in the United Kingdom | Novavax Inc. - IR Site, n.d.).
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NVX-CoV2373 Vaccine by Novavax Inc.

Adenoviruses are viruses that can cause the common cold. We as humans have them, monkeys have them, as do other animals. For years, people have been using these viruses to deliver DNA, which are instructions for proteins. For the COVID-19 vaccine, researchers swap in a gene from SARS-CoV-2. When the vaccine is given to someone, the modified cold virus makes the SARS-CoV2 protein, which stimulates the immune response. 
Fortunately, the protein does not make you sick. It does its job and leaves.

Adenovirus for COVID-19 by the University of Michigan Health Lab

Vesicular stomatitis virus is a virus that primarily infects livestock (cows, horse, pigs). Here, it is being used as a vector delivery system, much like the human or chimpanzee adenoviruses. The modified vesicular stomatitis virus delivers the instructions for the SARS-CoV-2 protein into cells. It has worked very well for Ebola, which is another SARS-CoV-2 virus.

Recombinant Vesicular Stomatitis Virus by the University of Michigan Health Lab

Pfizer and BionTech are producing two vaccine candidates being studied in adults ranging from 18-55 and 65-85 in a placebo-controlled, observer-blinded dose-escalation study with 2 doses over 21-day intervals.
- BNT162b1: encodes a secreted trimerized SARS-CoV-2 receptor-binding domain
- BNT162b2: encodes perfusion stabilized membrane-anchored SARS-CoV-2 spike

The process is to select a single vaccine candidate and dose level for use.

BNT162b1/BNT162b2 from Pfrizer and BionTech

[Currently 46 phase 2 trials so we can input these later]

INACTIVE: Phase 2 Vaccine Trials

From our Literary Review:

A recombinant subunit vaccine has entered the phase three clinical trials via the Institute of Microbiology under the Chinese Academy of Sciences. The co-developer is Anhui Zhifei Longcom Biopharmaceutical Co. Ltd. It had been approved for phase one clinical trials on June 19, 2020 and ended phase two at the end of October, in which 97% of trial participants developed high levels of neutralizing antibodies which is an indicator of immunity to the SARS-COV2 virus

The drug will be a recombinant subunit vaccine under the category of an adjuvanted recombinant protein subunit (RBD-Dimer) vaccine. It uses pieces of the SARS-CoV2 protein components to trigger a protective immune response. This vaccine will be able to induce humoral and a cell mediated immune response which is something that live attenuated and inactivated vaccines cannot do.

Since the vaccine does not contain a live pathogen, there is little risk to the vaccine (Vaccine to Undergo 3rd Phase of Trials, n.d.). On October 22, 2020, it was determined to be generally safe and effective based on data that was gathered from phase one and phase two. Phase 3 clinical trials as of November 20, 2020 in Xiangtan, Hunan Province.
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Anhui Zhifei Longcom / Chinese Academy Vaccine

- Contains replication-defective Ad5 vectors expressing the full-length spike gene (S) based on Wuhan-Hu-1 (YP_009724390)
- Phase 2 Trials show vaccine dosage at 5 x 10^10 viral particles is safe and effective in inducing significant immune responses after a single immunization. 
- Completed phase 2 trials and planning on phase 3

*****
From our Literary Review:

Adenoviral vectors, armed with forgien genetic material, are already widely used in vaccines and cancer treatments (Zhang & Zhou, 2016). Ad5-nCoV, or Cansino, is a vaccine for COVID-19 that was developed in China by CanSino Biologics. Cansino was one of the first coronavirus vaccines to be tested in humans, beginning March of 202 and ending May of the same year. April 11, 2020 was the start of a randomized, double blind, placebo controlled phase II clinical trial. The middle and low doses tested exhibited a significant neutralizing antibody response with seroconversion of neutralizing antibodies of 59% and 47% respectively and seroconversion of binding antibody of 96% and 97% respectively. At 28 days post vaccination 95% of the middle and 91% of the low dosage groups showed cellular or humoral immune responses.
Ad5-nCoV uses replication defective mutant adenovirus type 5 as a viral vector to express the SARS-CoV-2 spike protein, the main antigen component responsible for entry into the cell. The purpose of this structure is to have the common cold virus mimic coronavirus. 

Adenovirus based viral vector technology appears to be a preferred strategy for prevention of newer infectious diseases. Adenovirus vector based vaccine candidates for prevention of infectious disease are being tested more often in order to protect humans from infectious diseases. It has been seen to be one of the most effective vectors to deliver antigens to the host cells of mammals. In addition, it can also induce strong innate and adaptive immune responses, is easily manipulated, and has a reduced risk for insertional mutagenesis of the viral gene. Ultimately, Ad vectored vaccines have shown great potential as candidates in infectious disease prevention.


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