A Brief Introduction to Covid-19 Vaccines
Khusro Arastu, MD email@example.com December 2020
Types of Covid-19 Vaccines
• Active Immunity (Vaccination)
• Viral Vector (Oxford/AstraZeneca, CanSino Biologics, Janssen (J & J), Gamalaya-Sputnik)
• Live Attenuated (Codagenix, Indian Immunologicals Ltd.)
• Inactivated Virus (SinoVac, SinoParm)
• VPL (Virus Like Particles )
• Split Virus Vaccines (e.g. Flu Vaccines)
• Passive Immunity (Antibody Administration)
• Monoclonal Antibodies (e.g. Bamlanivimab)
• Polyclonal Antibodies (e.g. Regeneron)
• Convalescent Plasma
Vaccines in US (Phase 3)
Moderna* Pfizer* AstraZeneca* Janssen Novavax
* Completed Phase 3
Types of Covid-19 Vaccines in the Pipeline
ACTIVE IMMUNITY (VACCINES)
NUCLEIC ACID VACCINES
RNA Vaccines VIRALVectorVaccines
Viral Sub-Unit Vaccines Split Virus Vaccine VLP Vaccines
Live Attenuated Vaccines Inactivated Vaccines
Gene that codes for Viral protein
mRNA templete for Viral protein AharmlessVirusVectortransportsVirusgene
Virus Surface Protiens / subunits
Cut Pieces of the actual virus
Virus Like Particles without the Genetic material
Weakened Actual Virus Virus killed by heat/chemicals
Herpes Zoster, Hepatitis B, HPV, DPT Flu Vaccines
MMR, Chickenpox, Polio, TB Polio
Pfizer; Moderna AztraZeneca;CanSino,Janssen, Gamalaya
Novavax; AdaptVac, Clover Pharmaceuticals N/A
Codagenix, Indian Immunologicals SinoVac; SinoPharm
Status of the Vaccines
Bharat Biotech Oxford/AstraZeneca CanSino Gamaleya-Sputnik Janssen (J & J) Novavax
Moderna BioNTech / Pfizer Wantai – Xiamen Inovio
Viral Vector (Non-replicating) Viral Vector (Non-replicating) Viral Vector (Non-replicating) Viral Vector (Non-replicating) Protein Sub-Unit
Viral Vector (Replicating) DNA Vaccine
2 (0,14) 2 (0,21) 2 (0,28) 2 (0,28) 1 dose! 2 (0,21) 2 (0,21) 2 (0,21) 2 (0,28) 2 (0,28) 1 dose! 2 (0.28)
IM Intra-Nasal Intra Dermal
Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 2 Phase 2
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Why Multiple Vaccines ?
• A variety of COVID-19 vaccines are being developed around the world.
• According to WHO, as of November 12th 2020, there are 48 vaccines in Clinical Trials and 164 candidate vaccines in Pre- clinical evaluations.
• All of them share one thing in common: they all stimulate a primary immune response so that the body can develop memory B and T cells against the SARS-CoV-2 virus.
• The development of immune memory by vaccines is what will protect the person against subsequent COVID-19 infection.
• Each COVID-19 vaccine has distinct advantages and disadvantages, but the development of different COVID-19 vaccines provides some redundancy and overlap.
• In case a vaccine is unsafe in humans or fails to protect people against COVID-19, the world has other COVID-19 vaccines that it can trial and produce.
• It is this pursuit of multiple vaccines that will allow the global population to be immunized sooner, allowing COVID-19 to be eliminated so that the world can start to recover from the pandemic!!
CDC Phase 1 Vaccine Rollout Plans:
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21 million 3 Million
87 Million 100 Million 53 Million
Health Care Personel Nursing Home Residents
High Risk Medical Conditions Adults > 65 Years Old
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• Depending on how many times the body is exposed to the virus or vaccinated, the body can generate two types of immune responses.
• The body generates a primary immune
response when exposed to the SARS-CoV-2 virus for the first time or gets the 1st dose of the vaccine. The primary immune response is slow and weak as it takes days for the body to generate enough antibodies and T cells to eliminate the virus.
• However, the body generates long-lasting memory B and T cells that “remember” the SARS-CoV-2 virus, generating immune memory.
• When the virus enters the body for the second time or the 2nd dose of the vaccine is given, the body develop a secondary immune response. The secondary immune response is stronger and quicker than the primary immune response as memory B and T cells are rapidly activated.
• This results in higher antibody concentrations and T cell counts around the body to eliminate the virus more quickly, reducing the symptoms and severity of COVID-19. In addition, more memory B and T cells are produced after infection which strengthens memory of the SARS-CoV-2 virus.
• It is the development of immune memory that is key to how a vaccine works!!
Why Two Doses ?
The Global Picture
AstraZeneca 300 Million Moderna 100 Million Pfizer 100 Million Janssen 100 Million NovaVax 100 Million Sanofi-GSK 100 Million
The Different Kinds of Vaccines Explained
Types of Vaccines
• The SARS-CoV-2 outbreak has prompted the rapid expansion of several technology platforms, including DNA and RNA vaccines, never before clinically tested in humans.
• Rather than producing a viral protein in a
lab, delivered DNA or RNA directs our cells to make parts of viral proteins that do not cause disease, and the immune system then makes antibodies the same as it would had the protein been injected directly.
• Today, rapid production of DNA or RNA in large amounts only requires the sequence of the virus’s genetic material. The sequence of SARS-CoV-2 was identified and published by Chinese researchers on January 11th, 2020.
• Also novel vaccines are being developed like the Protein Sub-unit Vaccine and Split virus vaccines. Production of Virus-Like Particles to mRNAs making Antibodies directly.
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• DNA vaccines are made up of small strands of DNA, a gene, encoding the antigen of interest (in this case Spike Protein or S-Protein, of the Covid-19 Coronavirus).
• The Gene is attached to a plasmid for delivery into the body. The Plasmid is used so that the body does not degrade the foreign gene before it can provoke an immune response.
• Once administered the DNA are taken up by host cells which produce the S-Protein, and show the antigen (S-Protein) on its cell surface, thus stimulating an antibody and T cell response.
• Inovio Pharma (USA) is developing the DNA vaccine INO-4800.
Gene for the S-Protein
Transcribed to mRNA
Translated to S-Protein
Host Antibody Response
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Lipid Nanoparticle (LNP) with mRNA inside
• RNA vaccines consist of an mRNA encoding the antigen of interest (The SARS-CoV-2 Spike protein or the S-Protein. This is placed in a Lipid Nanoparticle (LNP) vehicle. The LNP prevent the mRNA degradation by the host until it is taken up by the cell.
• Once administered the RNA are taken up by host cells. The intra-cellular lipases degrade the LNP exposing the mRNA. The mRNA is then translated into the S-protein, and is on its cell surface, stimulating an antibody and T cell response.
• Moderna has developed the RNA vaccine mRNA-
1273 encapsulated in a lipid nanoparticle. The RNA used is the viral RNA, Isolated and spliced to give the exact gene.
• Pfizer/BioNTech, RNA Vaccine uses an mRNA that is genetically engineered in the Lab from the Sequenced viral genome.
• Both vaccines carry the foreign gene for whole S protein.
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Host Antibody Response
RNA & DNA Vaccines
• DNA and RNA vaccines, however, present some challenges. As there are currently no approved DNA or RNA vaccines, it is unclear how effective they will be in vaccinating a population against COVID- 19 or how quickly they can be scaled up.
• In addition, naked genetic material alone is unlikely to produce strong immune responses and memory as they can be quickly degraded outside cells and need to cross cell membranes to produce and shuttle the antigen on the cell surface.
• There are also safety concerns that DNA or RNA vaccines can persist in the body for a long period of time and may incorporate into the host’s genome. This can mutate cells, leading to the development of tumor cells or malignancies.
• Viral vector vaccines are similar to live-attenuated vaccines in that they use a harmless virus or an attenuated virus known as a vector.
• However, the attenuated virus carries a foreign gene in their genome representing the antigen of interest. For example the Spike Protein in SARS- Cov2.
• When the virus infects a cell, they administer this foreign gene into the cell. The cell then transcribes and translates the gene to produces the antigen, and display the antigen on the cell surface to stimulate an immune response.
• The infected cell may also slowly reproduce the virus which allows more cells to become infected and display the antigen on its surface.
• The Oxford/AstraZeneca, Gamalaya-Sputnik and the Janssen vaccines are all Vector Vaccines.
The viral Genes inserted into a harmless virus
Harmless Viral Vector carrying Corona Virus Genes
• Similar to live-attenuated vaccines, viral vector vaccines can stimulate strong antibody and T cell responses as the virus is able to (slowly) infect cells to produce and display the S protein on the cell surface.
• This allows both B and T cells to be activated, producing strong immune responses and memory.
• There are some obstacles, though, in approving viral vector vaccines for use in humans. Like live-attenuated vaccines, viral vector vaccines cannot be used in immunocompromised or immunosuppressed people as the immune system is unable to contain the slow replication of the viral vector.
• The viral vector vaccine may also be less effective in people with pre-existing antibodies against the viral vector, preventing it from infecting cells to generate immune memory against the SARS-CoV-2 virus.
• Viral vector vaccines are quite complicated to produce. They require specialized facilities to produce the viral vector vaccine and maintain its purity.
• The Vectors with the inserted gene are considered a genetically modified organism (GMO) that carries a potential risk to the environment, it is also subject to strict environmental regulation and risk management.
• Viral vector vaccines are a new vaccine technology with only one vaccine of this type currently approved for clinical use. Dengvaxia is a dengue vaccine that consists of two genes from the dengue virus being expressed in an attenuated yellow fever 17D viral strain. The vaccine is only given to people who were previously infected with dengue as it has been shown to cause severe complications and dengue infection among uninfected people.
• Two well-known COVID-19 vaccine candidates are viral vectors, both of them possessing the foreign gene for the S protein.
• AZD1222, developed by Oxford University, in partnership with AstraZeneca contains a gene for the whole S protein that is expressed in a non-replicating chimpanzee adenovirus.
• Gam COVID Vac (Sputnik) is another COVID-19 viral vector vaccine that is developed by Gamaleya Research Institute, Russia. The vaccine consists of the gene for the whole S protein that is contained in two different recombinant human adenoviruses administered separately.
Live Attenuated Vaccines
• Live attenuated vaccines contain a live but less infective form of the pathogen. These vaccines have all the components of the original pathogen, but they possess mutations that reduce their ability to replicate inside the body, so they will not reproduce natural infection.
• It is a proven vaccine technology used to vaccinate people against many infections such
as polio, tuberculosis and chicken pox.
• As of the beginning of September 2020; however, only three COVID-19 vaccines are live attenuated vaccines with none entering clinical trials in the U.S.
• One of these is being developed in Griffith University, where parts of the SARS-CoV-2 genome are mutated to reduce but not abolish the ability of the SARS-CoV-2 virus to replicate in human cells.
• Codagenix and Indian Immunological Ltd are developing Live Attenuated Vaccines which are also not in clinical trials.
Virus is alive but rendered less infective but still able to provoke a robust immune response
Live Attenuated Corona Virus
Live Attenuated Vaccines: Advantages & Disadvantages
• There are also disadvantages associated with a live attenuated COVID-19 vaccine. The production of live attenuated vaccines requires biosafety-level facilities to safely produce the vaccine.
• Cold storage facilities are also required to maintain stability of a live attenuated COVID-19 vaccine, limiting the global distribution of the vaccine.
• Also,aliveattenuatedCOVID-19vaccinecannotbe given to immunocompromised or immunosuppressed patients as the attenuated SARS- CoV-2 virus can slowly replicate, exceeding the immune system’s ability to contain the pathogen.
• Lastly, there is the risk that the attenuated SARS-CoV- 2 virus can accumulate mutations while it replicates to revert back to its infective form, reproducing infection. This is the case for the oral polio vaccine. As it accumulates mutations inside the body, the vaccine can become pathogenic to humans.
causing vaccine-derived polio.
• Live-attenuated vaccines present advantages to combating COVID-19.
• A single dose of the vaccine is sufficient to protect the person against COVID-19 as it has all the components of the original SARS-CoV-2 virus to generate strong antibody and T cell responses.
• This generates long-lasting immunity to COVID-19 due to the mass proliferation of memory B and T cells. At the same time, a live attenuated COVID-19 vaccine, once approved, can be quickly produced at scale as existing methods and facilities are available to produce live attenuated vaccines.
• Evolving from live-attenuated vaccines that are able to (slowly) replicate in the body, inactivated vaccines contain a whole pathogen that is killed or inactivated by chemical, heat or radiation.
• This eliminates the possibility of the pathogen replicating and possibly causing infection, yet the vaccine still has all the components of the original pathogen to induce a memory response.
• Various inactivated vaccines are available to vaccinate people against infections such
as cholera and hepatitis A.
• Following in these footsteps is CoronaVac, produced by Sinovac R&D Co.
• CoronaVac contains the inactivated SARS-CoV-2 virus that is combined with alum (aluminium salt). Alum acts as an adjuvant to stimulate immune responses against the vaccine.
Virus is killed/ inactivated by chemicals , heat or radiation
Dead Corona Virus
Cant replicate but provoke a host immune response
Inactivated Vaccines: Pros & Cons
• On the other hand, as the inactivated pathogen cannot replicate inside the body, more than one dose of the inactivated vaccine is required to give the body time to develop immune memory against the SARS-CoV-2 virus.
• In addition, specialized biosafety-level facilities are needed to firstly grow the pathogen and then inactivate it at scale.
• Lastly, inactivation of the pathogen may alter the shape of the antigens which may be different from the original version. Hence, the body may not generate the correct immune memory response against the original SARS-CoV-2 virus.
• Inactivated vaccines are considered safer to use than live-attenuated vaccines with fewer side effects.
• This is because the vaccine components cannot replicate inside the body, eliminating the possibility of infection.
• Inactivated vaccines can also be stored at room temperature as the pathogen is dead and non- replicative. This eliminates the need for refrigeration, allowing the vaccine to be distributed to more remote areas of the world.
Viral Subunit Vaccines
• Subunit vaccines take parts of the pathogen (antigens) that simulate an immune response and inject them into the body.
• Most subunit vaccines consist of proteins from the pathogen (such as the SARS-CoV-2 S protein, but they can also be fragments of bacterial toxins (toxoids) or pathogenic components such as the cell wall.
• Two of the COVID-19 vaccine candidates are subunit vaccines: NVX-CoV2373 developed by Novavax and SCB- 2019 developed by Clover Biopharma.
• Both vaccines contain the whole S protein of the SARS- CoV-2 virus combined with an adjuvant, a chemical that enhances the immune response to the vaccine.
• Subunitvaccinesproducestrongantibodyresponsesas the antigens are collected, processed and presented to B cells to stimulate antibody production.
• Nevertheless, they are safe to administer as the whole pathogen is not injected, so it will not cause infection.
• Lastly, they are simpler and cheaper to produce as only parts of the pathogen need to be produced.
Viral proteins particularly the spike proteins are extracted and made into a vaccine
Viral Subunit Vaccine
VLP Vaccines (Virus Like Particle Vaccines)
• Virus-like particle: This type of vaccine contains molecules that mimic the virus but are not infectious and, therefore, not a danger. VLP has been an effective way of creating vaccines against diseases such as human papillomavirus (HPV), hepatitis and malaria.
• Virus-like particles (VLPs) are nanostructures (lipids NPs, dendrimers and fullerenes) that resemble the structures of viruses.
• They are composed of one or more structural proteins that can be arranged in several layers and can also contain a lipid outer envelope. VLPs trigger a high humoral and cellular immune response due to their repetitive structures.
• A key factor regarding VLP safety is the lack of viral genomic material, which enhances safety during both manufacture and administration.
• Contemporary VLP production may take advantage of several systems, including bacterial, yeast, insect and mammalian cells.
Viral Like Particles are synthetically manufactured to mimic the virus and hence provoke the host immune response
Virus Like Particle
• The vaccine is made by cutting the virus into several pieces.
• All the pieces of the virus are present, but they can’t cause disease.
• The only example of this kind of vaccine is the flu vaccine.
• No company is currently working on the split Virus Vaccine technology for the coronavirus
• Advantage: the virus is inactive, while all elements remain present
• Disadvantage: it’s difficult to determine the right dose. Moreover, this type of vaccine is not easy to produce
The whole Virus is cut into multiple pieces
Fragmented Corona Virus
mRNA Induced Antibody
• This is another novel vaccine concept being explored by M.I.T.
• The mRNA here is not coding for the antigen of interest (e.g. the viral Spike Protein), instead it codes for the actual antibody.
• The mRNA enters the host cell and makes multiple copies of the antibody (against the Virus).
• This process bypasses several steps of the immune response and makes the antibodies directly for the host.
• Risks and benefits are similar to the other RNA vaccines except that it behaves like passive immunity (by producing the antibody itself) and may have a faster response.
Translated & Amplified to directly produce Immunoglobulin
Antibody against Corona Virus
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DNA Vaccine RNA Vaccines Viral Vector
VIRUS / PROTEIN
Live Attenuated Inactivated Viral Sub-Units
Special Delivery System Syringe/Needle Syringe/Needle
Syringe/Needle Syringe/Needle Syringe/Needle
Two Doses Two Doses Two Doses
One dose Two Doses One dose
• Most of the vaccines are intra-muscular, but some are intranasal (Nasal spray), intra-dermal, subcutaneous or even oral (capsules)
Risks, response and ease of production:
DNA Vaccine RNA Vaccines Viral Vector
VIRUS / PROTEIN
Live Attenuated Inactivated Viral Sub-Units
Risk of integration/Mutation Safe
Risk of integration/Mutation
Risk of infection Safe
Medium Strong Strong
Robust response Strong Strong
Special Facility Ease of Production Easy to produce
Easy to produce Special Facilities Easy to produce
The Pipeline: Clinical Trials to Distribution
• Vaccine development moves through established pipelines that require rigorous safety and efficacy testing before public availability. After identification of a vaccine candidate, pre-clinical studies in cultured cells and animals ensure the vaccine elicits an effective immune response without being toxic, before clinical trials begin in humans. At this point, the FDA recognizes the vaccine as an Investigational New Drug (IND).
• The Phase 1 Clinical Trial assesses risk factors or adverse effects, what dose is required, whether this dose is the same for different individuals, and if the vaccine promotes healthy immune systems to make antibodies. The Phase 1 trial for the Moderna vaccine began in record time, just two months after the sequence of the virus was published.
• If there are no risk factors or adverse effects in Phase 1 trials, Phase 2 and Phase 3 trials expand to more volunteers, increasing statistical power. Each phase
has built-in objectives and endpoints and volunteers are monitored for months. After Phase 3, the vaccine must receive FDA approval before licensing and distribution.
• Then, Phase 4 Clinical Trials is the last phase and includes ongoing studies of risk and side effects after the vaccine is distributed.
• Once available, vaccine distribution follows guidelines recommended by the CDC (Centers for Disease Control) and developed by the Advisory Committee on Immunization Practices (ACIP).
• Vaccine distribution areas include the 50 states, District of Columbia, and eight US territories. During the H1N1 pandemic in 2009, doses were distributed according to population in each distribution area.
• The CDC recommends vaccinating the highest-risk populations first. A priority list is then phased out.
• Before a vaccine is widely available, Compassionate Use Authorizations (CUA), Emergency Use Authorizations (EUAs) and the strategic national stockpile are designed to streamline responses during a crisis and mitigate the most severe cases.
• BARDA (Biomedical Advance Research & Development Authority), a government agency, provides national funding for companies and programs dedicated to developing drugs, vaccines and antivirals.
• The FDA (Federal Drug Administration) issued
EUAs authorizing use without trials and testing for healthcare professionals to test patients for antiviral drugs.