COVID-19 Vaccine

An antigen is a protein on the surface of microbes against which specific antibodies are formed. The immune system then destroys the antigen to stop the progression of the disease.

Antigen selection is the first step in vaccine development. There are various types of antigens that are currently being considered for use in developing COVID-19 vaccine. Here is a list:

Whole-cell antigen

A whole-cell antigen, as the name suggests, has the whole virus - nucleic acid (DNA/RNA), protein, lipids and other components. A whole-cell vaccine is of two types:

• Live attenuated vaccine - which uses a weaker version of the original virus.
• Killed virus vaccine - which uses the killed virus.

Live attenuated vaccines are generally more effective and one or two doses of the vaccine can give lifelong immunity. On the other hand, killed vaccine needs booster doses to ensure that the person is immune to the pathogen. 

Structural proteins

Structural proteins are one of the most common targets for vaccines. These proteins are needed to make a complete virus. The SARS-COV-2 virus codes the following structural proteins: 

• Spike (S) protein
• Nucleocapsid (N) protein
• Membrane (M) protein 
• Envelope (E) protein

S protein

The S protein is being used as a target for a lot of COVID-19 vaccines. It is the protein that helps SARS-COV-2 virus bind with the ACE-2 receptors on the surface of human body. S protein has 2 subunits - S1 and S2. 

The S1 subunit further has two domains - the N-terminal domain (NTD) and the C-terminal domain (CTD). A part called the receptor-binding domain is present in the CTD, this is the part that binds to the ACE-2 receptors.

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The S2 subunit contains all the parts that the virus needs to fuse with the outer membrane of healthy cells - viruses are intracellular parasites, they have to enter healthy cells and use all the machinery of body cells to be able to replicate.

Various antigens are recognised from the S protein. These include:

Full-length S protein

This antigen has the complete S protein with all of its subunits. Since a complete protein will have more sites that could be identified by the immune system, it elicits a strong antibody response. A DNA vaccine encoding the full length S protein has shown promising results in animal studies in the form of higher antibody titers and reduced overall symptoms. 

The UK based pharmaceutical company GSK (GlaxoSmithKline) is working together with the Chinese firm Clover Biopharmaceuticals to make a full-length S-protein vaccine for COVID-19.

RBD

Since the receptor-binding domain is what helps the SARS-COV-2 virus bind to the ACE-2 receptors, it is one of the common targets of vaccine developers right now. Injecting a person with either the protein or a nucleic acid coding for this subunit will lead to the production of antibodies against it. In case the person is exposed to the virus then, the antibodies would quickly recognise the subunit and prevent it’s binding to the ACE-2 receptors. This protects the person from acquiring the disease.

S1 subunit

Since it contains the RBD, the whole S1 subunit is also being considered a vaccine candidate for COVID-19. 

Animal studies with MERS virus have shown that introduction of S1 subunit provided complete protection from the MERS-COV infection. 

The S1 subunit also has the NTD domain which has shown some immunogenicity (ability to elicit an immune response) in lab studies with MERS virus though it was not a candidate for COVID-19 vaccine since not much is known so far about the function of NTD in SARS-COV-2. 

Baylor Collge of Medicine, US, is developing a vaccine candidate with the S1 or RBD protein and an RNA vaccine encoding the RBD protein of the SARS-COV-2 virus is being developed in China. 

FP domain of the S2 subunit

The FP domain is the part of the S2 subunit that helps SARS-COV-2 virus fuse with the membrane of (and hence enter) healthy cells. 

Tianjin University in China is working on an RBD-FP fusion protein vaccine. Animal studies have shown that the vaccine is highly effective in creating antibodies against the virus. 

Nucleocapsid (N) protein

N-protein is one of the most conserved proteins in all coronaviruses - it does not change much and is almost the same in all coronaviruses. Studies show that about 89% of the patients with SARS have antibodies against this protein. The N-protein performs various functions in COVID-19. This includes the formation of the outer coat of the virus, replication of the viral RNA and release of new viruses from the infected cell - these new viruses then infect the neighbouring cells and spread the disease in the patient’s body. 

However, there is a lot of controversy around the use of this protein for a vaccine. As per the WHO draft for candidate vaccines for COVID-19 no institute has specifically mentioned using N protein so far.

Membrane (M) protein and envelope (E) protein

Just like N protein, M protein is highly conserved in coronaviruses and is a potential candidate for the vaccine of COVID-19. The M protein plays an important role in the assembly of viruses in infected cells. 

On the other hand, E protein is not a strong immunogen, though it is responsible for assembly of SARS-COV-2 virus and budding out of the virus from the infected cell. 

Studies show that removal of the E protein reduces the infectivity of coronaviruses and their ability to elicit inflammation. 

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Live attenuated vaccines

As already mentioned, these vaccines are weaker versions of the live virus and they create a strong immune response. Live attenuated vaccines are usually created by using computer programs that find changes in the genetic code of the virus that would be needed to weaken it. Using a single program, a number of such changes can be traced that would then serve as options for creating vaccines. 

A live attenuated vaccine against COVID-19 is being developed by the Serum Institute of India, in collaboration with the US-based biotechnology company Codagenix Inc that specialises in creating viral vaccines based on the genome of the virus.

Subunit vaccines

These vaccines use various subunits in the virus which have a strong capacity to stimulate an immune response. The whole S subunit vaccine is an example of the subunit vaccine.

Vector vaccines

These vaccines are somewhat similar to the live attenuated vaccines. However, unlike the live attenuated vaccines, vector vaccines use another virus that causes a milder disease to carry an immunogenic subunit of the target virus. 

Adenovirus is one of the most common viruses to make vector vaccines. These viruses cause mild disease in even immunocompromised people, which can be negated by introducing certain changes in the genome of the virus. The code for the target subunit is then added into the nucleic acid of the vector. Adenoviruses affect various types of body cells and are fairly easy to grow in large numbers in tissue cultures, which makes them an excellent vector for mass development of vaccines.

Greffex Inc, a US-based firm has produced an adenovirus-based vaccine candidate for COVID-19. However, this one is non-replicating - it would not divide or make copies of the virus in the person’s body. Non-replicating adenoviruses generally need higher doses to confer immunity than a replicating adenovirus. A non-replicating adenovirus vaccine has already entered phase 1 clinical trials. The vaccine is being developed in China.

Another vector vaccine is being developed using the Horsepox Virus codes for the S protein of SARS-COV-2. Horsepox virus causes skin eruptions in horses. It is a relative of the small pox and cowpox virus. 

RNA/DNA vaccines

Nucleic acid vaccines is a much recent technology that is said to be much more promising than the conventional live attenuated approaches. Though no RNA or DNA based vaccine has been approved for human use yet, researchers have continuously been working on the technology for a while now. 

DNA is the carrier of genetic information in a body cell. It codes for various molecules needed for the growth and development of the human body. However, DNA stays inside the nucleus of the cell - an organelle present in every cell of the human body. It is RNA, specifically mRNA - messenger RNA - that takes the message of DNA outside the nucleus into the cell and helps produce proteins. 

DNA/RNA vaccines contain the code for the antigen (the S protein for example) which produces the said protein/antigen when introduced into the body cell.

DNA vaccines are a bit easier to make and introduce into the body as compared to RNA vaccines. However, the former carries the risk that the new DNA gets integrated into the host genome and cause mutations. RNA vaccines, on the other hand, pose no such risk. Since the RNA quickly gets degraded after producing the protein/antigen, it does not pose any risk. Furthermore, scientists can modify the mRNA in their own way to reduce or improve their immunogenicity and both RNA and DNA vaccines can be produced in large numbers in the lab easily.

The Moderna vaccine candidate that has entered the phase 1 clinical trials is an mRNA vaccine. Various DNA and RNA vaccines are in their pre-clinical phases right now.

Synthetic peptide vaccine

These vaccines are a bit like subunit vaccines. However, instead of containing the whole subunit/protein, these vaccines have specific epitopes - the part of the antigen to which antibodies attach. Since these vaccines have low molecular weight (are lightweight molecules) and are complex, they need adjuvants to improve their function. Adjuvants are substances that modify (in this case improve) the action of another agent (the vaccine in this case).

Right now, a Canada based firm, Generex Biotechnology is working on developing a synthetic peptide vaccine for COVID-19. 

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The World Health Organisation has recently released a document describing what a preferred vaccine candidate for COVID-19 is like and what all features could be minimally tolerable. Here is what the document says:

• The vaccine should be made for use for both at the time of an outbreak (to save at-risk people and to contain the spread of COVID-19) and for long-term use.
• The target population should be all adults in all age groups, preferably including pregnant and nursing women. The vaccine must give protection to the elderly.
• Ideally, the vaccine should not have any contraindications. However, some contraindications like that for immunocompromised people may be minimally tolerated.
• The vaccine should be highly safe to use or its benefits should outweigh the risks. It should not have any serious after-effects or only mild/transient adverse effects both for outbreak control and long term use.
• The vaccine should ideally have a 70% efficacy on the basis of a population in a given area. However, if that is not possible, the efficacy should be clearly mentioned with a 50% point estimate. It should show consistent results in the elderly. 
• The efficacy of the vaccine should be clearly assessed like what would the vaccine do would it reduce the transmission of the virus or viral shedding etc.
• The vaccine should ideally provide quick protection against the virus (less than 2 weeks). It should not have a regimen of more than two doses. Booster doses are allowed but they should have a low frequency, yearly or farther spaced. In case of booster doses, the primary vaccine should preferably be a single dose. 
• One dose of the vaccine should provide protection for a year or at least 6 months.
• The vaccine can be administered through any route including injections. However, non-parenteral - oral, intranasal, anything not through a syringe - is preferred for the ease of administration.
• The vaccine should preferably be stable at higher temperatures for the ease of transportation. It should ideally have a vial monitor. Vial monitors indicate whether the vaccine has been kept at ideal temperatures. They help determine the viability of the vaccine.
• The vaccine should have a shelf life of a year at -60 to -70 degree Celsius and about 2 weeks at 2 to 8 degree Celsius. For long term use, the vaccine could be stored at -20 degree Celsius or higher.
• In the long term, the vaccine should be coadministered with other vaccines like that of polio, measles and pneumococcal vaccine. Though it could be a stand-alone vaccine.
• Multidose vials of vaccines are preferable - a vial containing more than one dose of the vaccine - for immunization campaigns. However, for long term use both single and multidose vials can be used. The multidose vials should be properly handled and discarded after 6 hours of opening the vial or at the end of immunization session (whichever comes first) unless the vaccine is approved by the WHO to be used for 28 days after opening the vial or if has other specific guidelines for use.
• The vaccine injection should not have more than 0.5 mL of vaccine, though it could go up to 1 mL.
• The vaccine should be able to be produced in large amounts and at a cost that allows for wide distribution in the outbreak situation.

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