- 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

- 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. 

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.

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.

INO-4800 (NCT04336410) by Inovio Pharmaceuticals

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

- 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

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) 

[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

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


- 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

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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.


Ad5-nCov vectored COVID-19 Vaccine by CanSino Biologics

Sputnik V by The Gamaleya Center

- 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



Michigan State University

Carnegie Mellon University

University of California, Santa Cruz

University of Pittsburgh

University of Michigan - Ann Arbor

Bowdoin College

- Development of COVID-19 Vaccines
- Types of Vaccines:
     - Virus Vaccines
     - Nucleic Acid Vaccines
     - Viral Vector Vaccines
     - Subunit Vaccines

Genetic Engineering in Vaccine Development 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

Nucleic Acid Vaccines use genetic material (DNA/RNA) from a viral protein that induces an immune response. The nucleic acid is inserted into human cells, which create copies of the virus protein. For many COVID-19 vaccines in development, the nucleic acid codes for the virus's spike protein. Both DNA and RNA vaccines trigger CD8+ cytotoxic T cell response to eradicate virus, in addition to antibody and CD4+ T cell responses.
However, because of their remarkable risk of failure, not a single nucleic acid vaccine has ever been licensed.

Some types of nucleic acid vaccines include (image):

Nucleic Acid Vaccines for COVID-19

Viral-Vector vaccines genetically engineer another virus, referred to as vectors, to carry genetic materials from the coronavirus and produce coronavirus proteins in the human body. These vectors are weakened and does not cause disease. Two main types are (shown in image):

Viral-Vector Vaccines for COVID-19

Virus vaccines use the virus itself, or  in a weakened or inactive form.

Virus Vaccines for COVID-19

Recent efforts to find a possible working vaccine for COVID-19 has allowed vaccine development to be distinct from traditional vaccines. Traditional vaccines for most viruses are either virus-based or protein-based. The idea behind next-generation vaccine platforms is to be able to develop a vaccine based on only sequence information and not by culturing the virus. Some of the non-traditional vaccines currently being developed are viral vector, nucleic acid-based vaccines and antigen-presenting cells.

New methods for COVID -19 vaccine development

Includes the scientific challenges and direction the development of COVID-19 vaccines.
- Challenges of development
- Vaccine antigen selection and design 
- Protective immunity 
- Preclinical evaluation of safety
- Manufacturing 
- Vaccine design itself is complicated
- Need for cold chain
- Consideration of cost
- Global distribution
-Authorization by US Food and Drug Administration and VRBAC
- Goals of development

Development of COVID-19 Vaccines

Nanotechnology is used to create modern vaccines because nanomaterials are best for antigen delivery. Nanotechnology advances have helped novel vaccine candidates to clinical trials at a surprising speed. Nanotechnology and viruses work at the same length scale, which specifically helps vaccine development. mRNA vaccine being developed is delivered through lipid nanoparticles.

Nanotechnology in vaccine delivery

Subunit vaccines use only the essential antigen or other purified protein subunits of the pathogen via a harmless vector that can best stimulate the immune system. The chance of developing an adverse reaction is significantly lower than in other vaccine types and they elicit a strong immune response. However, they often require adjuvants to stimulate an adequate response and it is difficult to identify the precise antigens that induce long-term immunity.

Subunit Vaccine

Vaccine Candidates of Interest (Lit Review)

• DNA vaccine consists of delivering genes or fragments of it, encoding immunogenic antigens to the host's cells by using DNA plasmids as a vector.

• Compared with traditional live or attenuated vaccines, DNA vaccines have several advantages, such as induction of broad immune responses without any risk being associated with replicating microorganisms; stimulation of both cellular and humoral immunity; construction of a vector encoding different antigens in a single vaccine; efficient large-scale, low-cost, production; and high storage stability

• A clinical trial was designed to evaluate the safety and tolerability of orally immunized bacTRL-Spike vaccine in healthy adults. However, this study has not yet started recruiting, and the estimated completion date is December 31, 2021 Moreover, the safety and immunogenicity of GX-19, another DNA vaccine against COVID-19 that uses intramuscular immunizations are already in clinical trials.

• mRNA vaccines do not need to reach the cell nucleus like the DNA ones, which is one of the potential practical advantages. The mRNA-1273 (Moderna Inc. Cambridge, MA, USA) was the first mRNA vaccine to be designed against COVID-19 and has achieved a time record of 63 days from vaccine design to human trials.

• Developing vaccines against COVID-19 require further studies on gene mutations and how to avoid vaccine failure because of them.

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