BASICS OF COVID-19 VACCINES: UPDATE AND REVIEW
Bs Phan Thượng Hải's Study
I. UPDATE
(Sept 1, 2021)
a. Vaccines in use in the world
* Nucleic Acid Vaccines = Genetic Vaccines
1. Pfizer (NY based) Biontech (Germany) and Fosunpharma (Chinese drug maker): used mRNA.
Economic Name: Pfizer BioNTech.
Scientific Name: Comirnaty.
Produced from USA and Germany.
In Use in 115 countries, including USA and Germany.
Efficacy from the study: 95% against symptomatic disease after 2 doses of muscle injection (IM), 3 weeks apart. Some reported 92%.
2. Moderna and NIH (National Institute of Health): used mRNA (messenger RNA).
Economic Name: Moderna.
Scientific Name: mRNA-1273.
Produced from USA.
In Use in 68 countries including USA.
Efficacity from the study: 94.5% against symptomatic disease after 2 doses of IM, 4 weeks apart.
* Viral Vector Vaccines
1. AstraZeneca (British-Swedish company) and University of Oxford: used Chimpanzee Adenovirus (called ChAdOx1).
Economic Name: Oxford AstraZeneca - known as Covishield in India.
Scientific Name: AZD1222.
Produced from Great Britain.
In Use in 182 countries including Great Britain.
Efficacy from the study: averaged 70% against symptomatic disease (62-90%) after 2 doses of IM, 4-12 weeks apart. Later report is 85%.
2. Gamaleya Research Institute, part of Russian Ministry of Health: used combination of 2 adenovirus (Ad5 and Ad26).
Economic Name: Gamaleya - Sputnik V.
Name: Gam-Covid-Vac
Produced from Russia
In Use in 47 countries including Russia..
Efficacy from the study: 91.6% (92%) against symptomatic disease after 2 doses of IM, 3 weeks apart.
3. Johnson and Johnson and Beth Israel Deaconess Medical Center (in Boston): used Adenovirus 26 (Ad26).
Economic Name: Johnson & Johnson.
Scientific Name: Ad26.COV.S 72
Produced from USA
In Use in 45 countries including USA.
Efficacy from the study after 1 dose IM*: 66% at preventing symptomatic disease (72% in USA, 66% in Latin America, 57% in S. Africa); 85% at preventing severe disease;100% against hospitalization and death.
4. CansinoBio (Chinese) and Instite of Biology at the country's Academy of Military Medical Sciences: used Adenovirus (called Ad5).
Economic Name: CanSino - Tianjin CanSino.
Scientific Name: Convidecia.
Produced from China.
In Use in 4 countries including China.
Efficacy from the study: 66% at preventing disease. Single dose IM*.
* Protein-based Vaccines
1. Bektop (Vector Institute), a Russian biological research center: used small portions of viral proteins, known as peptide.
Economic Name: Vector Institute (EpiVacCorona).
Scientific Name: EpiVacCorona.
Produced from Russia.
In Use in 2 countries including Russia.
Efficacy from the sudy: 50% preventing disease. 2 doses IM in 3 weeks apart.
* Whole Virus Vaccine = Viral Vaccines
(All used Inactivated virus)
1. Sinopharm and Beijing Institute of Biological Products.
Economic Name: Sinopharm Beijing. (called VeroCell in Việt Nam)
Scientific Name: BBIBP-CoV
Produced from China.
In Use in 66 countries, including China.
Efficacy from the study: 79.34% after 2 doses IM, 3 weeks apart. Later report 73% preventing disease.
2. Sinovac Biotech (private Chinese company).
Economic Name: SinoVac.
Scientific Name: Corona Vac (formerly PiCoVacc).
Produced from China.
In Use in 39 countries including China.
Efficacy from the study: 50.38% after 2 doses IM, 2 weeks apart.
3. Bharat Biotech (India), Indian Council of Medical Research and National Institute of Virology.
Economic Name: Bharat Biotech - Covaxin (in India).
Sientific Name: Covaxin (BBV152A,B,C).
Produced from India.
In use in 6 countries including India.
Efficacy from the study: unkown but emergency use in India. 2 doses IM after 4 weeks apart.
Note: Novavax of USA is a Protein-based Vaccine (same as EpiVacCorona of Russia) but still not in use?
Novavax (Maryland-based, USA): used a viral protein of Coronavirus (spike protein).
Name: NVX-CoV2373
Efficacy from the study: 89.3% (against most variants) against symptomatic disease after 2 doses IM in 3 weeks apart.
b. Real Benefits of Vaccines
* Infection and Disease (from infection)
In theory,
Using peer-reviewed publications, reports, and news articles, IHME reviews available data to find how effective each of the available vaccines is at preventing various outcomes. “Vaccine efficacy” is not a single number – we capture:
(1) Prevention of infection: a vaccine’s efficacy at stopping transmission of the virus from one person to another. An exposed person will not contract the virus, and by definition they will also not develop symptoms or disease.
(2) Prevention of asymptomatic disease: a vaccine’s efficacy at preventing an exposed individual who contracted the virus from developing symptoms.
(3) Prevention of symptomatic disease: a vaccine’s efficacy at preventing an exposed individual from suffering the symptoms of COVID-19 infection.
(4) Prevention of severe disease and death: a vaccine’s efficacy at preventing an exposed person from developing serious symptoms that often require hospitalization and lead to death.
There's a difference between infection and disease.
Infection, often the first step, occurs when bacteria, viruses or other microbes that cause disease enter your body and begin to multiply.
Disease occurs when the cells in your body are damaged — as a result of the infection — and signs and symptoms of an illness appear.
In response to infection, your immune system springs into action. An army of white blood cells, antibodies and other mechanisms goes to work to rid your body of whatever is causing the infection. For instance, in fighting off the common cold, your body might react with fever, coughing and sneezing.
In practice,
Vaccines actually does not prevent the infection, this is the fact. After a person is vaccinated, he or she can get the infection anytime (known as Breakthrough Infection) but because of the adaptive immunity already created by the vaccine, the disease from this infection will be likely asymptomatic or less likely symptomatic but not or rarely severe to require the hospitaliztion
The benefit of vaccines (and the vaccination) practically is the prevention of symptomatic and mostly severe diseases which require hospitalization and lead to death. The vaccine protects a vaccinated person from symptomatic and mainly from severe disease. This is reason for which a person needs to get the vaccination.
A vaccinated person will not get the protection from getting the infection. A vaccinated person will get the infection depends on his or her frequent exposure to the infected people around this person. The vaccination can not protect this person from the infection. The number of the breakthrough infection is not depended from the number of the vaccination. A vaccinated still can get the breakthrouh infection.
Fully vaccinated people can contract coronavirus. These cases, known as breakthrough infections.
Because this is the second exposure to antigen (= infection), the secondary immune response is larger and faster. So the sickness or the illness or the disease (from the second infection) is much less severe.
The immune response is the treatment (antiviral therapy) of the infection (and the disease from the infection), not the prevention from the infection.
* Antiviral therapy
The adaptive immune response is the antiviral therapy. It kills the virus extracellularly and prevents the virus to enter the cell.
Because viruses MUST infect a host cell to carry out life-sustaining functions or to reproduce, they are not considered living organisms, although some can survive on surfaces for long periods. Viruses are essentially like a parasite, relying on a host cell to reproduce and survive.
When a virus infects a host cell, it uses its genetic material to “hijack” the ribosomes in the host cell. These are the cell structures that make protein. So instead of protein being made that can be used by the host cell, viral proteins are made.
The virus also takes advantage of other componentswithin the host cell, such as ATP (adenosine triphosphate) for energy, and amino acids and fats to make new capsids and assemble new viruses.
Once enough new viruses have been made, they burst out of the cell in a process called lysis, which kills the host cell. This is called viral replication and it is the way viruses reproduce.
Once new viruses have been made, they can go on to infect new host cells, and new hosts.
The secondary adaptive immunr response to the infection is larger and faster, either from (the Memory from) the previous natural infection or the vaccination.
In the Dutch study, researchers examined the COVID-19 lab tests of 161 breakthrough infections in 24,706 fully-vaccinated health workers between April and July. Delta caused most of the infections.
Roughly 85% of the 161 breakthrough infections were symptomatic, but none required hospital admission, the researchers said.
* Prevention of severe Covid-19 disease
Efficacy of vaccines at preventing severe disease for 2 groups of Covid-19:
Group 1 = D614G (ancestral type), B.1.1.7 (Alpha)
Group 2 = B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta)
Vaccine Group 1 (including Alpha) Group 2 (including Delta)
Pfizer BioNTech 92% 90%
Moderna 94% 93%
Oxford Astrazeneca 85% 83%
Johnson & Johnson 86% 85%
Novavax 89% 79%
Sputnik 92% 80%
EpiVacCorona 50% 43%
Sinopharm 73% 63%
CanSino 66% 57%
Covaxin 78% 68%
mRNA 91% 89%
All 75% 65%
(Data from IHME = Institute of Health Metrics and Evaluation)
* Questions and Answers about the secondary adaptive immunr response
1. How long it lasts?
Answer: Do not know yet. Probably 1 year or more.
2. How long it will decrease that a booster is needed?
Answer: Still be controversial. However, CDC already recommended a booster after 8 months for fully vaccinated persons.
3. Which one is better, from the previous natural disease or from the vaccination? Better means larger, faster, lasting longer, more effective (against new variants)
Answer: Still be controversial.
4. Do I need a vaccination or a natural infection to create my adaptive immune response?
Answer: If you do not have a natural infection you do need a vaccination. Do not try intentionally to get natural infection (to get infected) to create your adaptive immunity.
5. Because of the Cleveland Clinic research, I already had a natural infection, do I need to have a vaccination and when?
Answer: Physicians still strongly recommend patients to get the vaccination (unless having contraindication for vaccination). The time for vaccination possibly is 3 months after the natural infection?
(The Cleveland Clinic researchers said, in the context of a short supply of vaccines globally, “a practical and useful message would be to consider symptomatic COVID-19 to be as good as having received a vaccine,” adding that people who’ve had the coronavirus “are unlikely to benefit from COVID-19 vaccination.”).
II. REVIEW
a. Virus and Viral Infection
A microscope is required to see viruses and they are 10 to 100 times smaller than the smallest bacteria.
Viruses consist of a piece of genetic material, such as DNA or RNA (but not both) surrounded by a protein shell called a capsid.
Sometimes this shell is surrounded by an envelope of fat and protein molecules, and out of this envelope may project glycoprotein protrusions, called peplomers, which can be triangular, spiked, or shaped like a mushroom. These protrusions bind only to certain receptors on a host cell and determine what type of hosts or host cell a virus will infect and how infectious that virus will be.
SARs- CoV-2, Coronavirus causing Covid-19 disease, consists of:
Piece of genetic material = RNA and Nucleocapsid phosphoProtein
Envelope = Membrane glycoProtein + Small envelope glycoProtein
Protrusions = Hemagglutinin-acetylesterase glycoProtein + Spike glycoProtein
Because viruses MUST infect a host cell to carry out life-sustaining functions or to reproduce, they are not considered living organisms, although some can survive on surfaces for long periods. Viruses are essentially like a parasite, relying on a host cell to reproduce and survive.
When a virus infects a host cell, it uses its genetic material to “hijack” the ribosomes in the host cell. These are the cell structures that make protein. So instead of protein being made that can be used by the host cell, viral proteins are made.
The virus also takes advantage of other components within the host cell, such as ATP (adenosine triphosphate) for energy, and amino acids and fats to make new capsids and assemble new viruses.
Once enough new viruses have been made, they burst out of the cell in a process called lysis, which kills the host cell. This is called viral replication and it is the way viruses reproduce.
Once new viruses have been made, they can go on to infect new host cells, and new hosts.
As a virus, Coronavirus also must infect the cell to reproduce. Coronavirus use its Spike Protein to connect with the ACE2 receptor of the cell to get into the cell for the infection. The death of the infected cells by the virus is the disease of the virus infection. The example is Coronavirus infection cause Pneumonia disease.
b. Diagnostic Tests for Coronavirus
* We've grouped them by molecular versus antigen tests.
Molecular tests identify viral RNA (frequently, but not always, through PCR testing), while antigen tests detect viral surface proteins. Either type can yield "rapid" tests, but antigen tests are inherently faster
Although the PCR method can test whether someone is infectious, it also detects people who have the virus but are not likely to spread it. Antigen-based testing, by contrast, could help to rapidly identify people who have high levels of the coronavirus, which indicates those who are most likely to be infectious to other people.
However, antigen tests are not as sensitive as molecular tests, carrying a greater chance of false negatives. Indeed, the emergency use authorization for each of the antigen tests indicates use in symptomatic patients only.
Still, antigen tests are driving the point-of-care testing that many experts have urged. Most of these tests require the purchase of an instrument, but the machines are generally much smaller than PCR analyzers. Only the self-contained BinaxNOW, which is the size of a credit card, doesn't require instrumentation. The Trump administration has purchased 150 millions BinaxNOW tests from Abbott and is distributing them to schools and nursing homes.
* Molecular Tests
1. Abbott IDNow: EUA; IFU; sensitivity/specificity: 100%/100%; results in 13 minutes
2. Roche Cobas: EUA; IFU; sensitivity/specificity: 100%/100%; results in 3.5 hours
3. Hologic Panther: EUA; IFU; sensitivity/specificity: 100%/100%; results in 3 hours
4. Cepheid GeneXpert Xpress: EUA; IFU; sensitivity/specificity: 97.8%/95.6%; results in 45 minutes
5. Thermo Fisher TaqPath: EUA; IFU; sensitivity/specificity: 100%/100%; results in 4 hours
6. Labcorps: EUA; IFU; sensitivity/specificity: 100%/100%; results in 24 hours
7. Quest Diagnostics: EUA; IFU; sensitivity/specificity: 100%/100%; results in 1 hour
* Antigen Tests
1. Abbott BinaxNOW: EUA; IFU; sensitivity/specificity: 97.1%/98.5%; results in 15 minutes
2. Quidel Sofia: EUA; IFU; sensitivity/specificity: 96.7%/100%; results in 15 minutes
3. BD Veritor: EUA; IFU; sensitivity/specificity: 84%/100%; results in 15 minutes
4. Access Bio CareStart: EUA; IFU; sensitivity/specificity: 88.4%/100%; results in 10 minutes
5. LumiraDx: EUA; IFU; sensitivity/specificity: 97.6%/96.6%; results in 12 minutes
A key to the information:
EUA = emergency use authorization
IFU = instructions for use.
All sensitivity/specificity figures are manufacturer-reported and based on strict adherence to protocols for sample collection and handling.
Note that result turnaround times specify only how long it takes to obtain results after a sample is placed in the analyzer; it does not account for sample transportation, in-lab backlogs in processing samples, or reporting of results, which often make for significant delay.
c. Viral Infection and Adaptive Immunity
Coronavirus infection causes Immune response (Adaptive Immunity)
1. Specialized Antigen Presenting Cell (APC cell) engulf the virus and display portions of it to activate T-helper cell.
2. T-helper cells enable other immune response:
B cell makes Antibodies that can block the virus from infecting cells as well as mark the virus for destruction. (Humoral Immunity)
Cytotoxic T cells identify and destroy infected cells. (Cellular Immunity)
There are 2 kinds of Antibodies:
IgM appears early (1st week) after the viral infection but lasts less than 2 weeks
IgG appears later (2nd week) after the infection but lasts for months.
d. Adaptive Immunity and Vaccine
By definition, vaccine is a substance used as an antigen or creating an antigen to stimulate the production of antibodies and provide adaptive immunity against one or several diseases (from the infection of a virus or bacteria) without inducing the diseases.
Actually, vaccine is an antigen or creates an antigen for the APC cell to engulf and start the adaptive immune response. For the virus, especcially Coronavirus, it mainly finally based on:
B cell makes Antibodies to block the virus from entering the cell to infect causing disease.
T cell destroys the infected cell.
The adaptive immune response after the vaccination almost the same as the real viral infection.
There 2 ways to make vaccine for Coronavirus:
- The old way use Coronavirus to be the antigen, injected into the body: either weakened Coronavirus or inactive Coronavirus.
1. Viral Vaccine or Whole Virus Vaccine
- The 3 new ways use Proteins of Coronavirus, mainly Spike Protein, to be the antigen:
2. Viral Vector Vaccine: A different virus is genetically engineered so it has the genetic instruction to produce Coronavirus protein. Then it is injected into the body. Then the body will produce Coronavirus protein as Antigen.
3. Protein-based Vaccine: Coronavirus protein, as itself or in the form of protein shell (that mimics the Coronavirus outer coat), is injected into the body. Then the body have Coronavirus protein as Antigen.
4. Genetic Vaccine: A genetic instruction (RNA or DNA) to produce Coronavirus protein is injevted into the body. Then the body will produce Corona virus protein as Antigen.
e. Classification of Vaccines for Covid-19
* Virus Vaccine or Whole-virus Vaccines
Vaccines that use a weakened or inactivated version of the coronavirus to provoke immune response. They require extensive testing for safety because they can cause disease.
Weakened coronavirus
Inactive coronavirus
* Viral Vector Vaccines
Vaccines that use a (different) virus to deliver coronavirus genes into cells and provoke an immune response.
A virus such as measles or adenovirus is genetically egineered so that it can produce coronavirus proteins in the body, then these proteins create the immune response. These viruses are weakened so they can not cause disease.
There are 2 types: those that can still replicate within cells and those that can not because key genes have been disable.
Replicating viral vector such as weakened measles
Non-replicating viral vector such as adenovirus
* Protein-based Vaccines
Vaccines that use a coronavirus protein or a protein fragment to provide an immune response.
Coronavirus proteins (called protein subunits) inject directly into the body.
Fragments of proteins or protein shells (called virus-like particles) that mimic the coronavirus's outer coat can also be used.
* Genetic Vaccine = Nucleic Acid Vaccines
Vaccines that use one or more of the coronavirus's own genes to provoke an immune response.
Aim to use genetic instructions (in the form of DNA or RNA) for a coronavirus protein that promt an immune response. The nucleic acid (RNA or DNA) is inserted into human cells which then churns out copies of the virus protein; most of them encode the virus's spike protein.
In short:
inject a genetic instruction (DNA or RNA) into the body, then the body produces from this instruction one of the coronavirus's protein (such as spike protein),
then this protein of corona virus will stimulate immune response from the body (like the protein-based vaccines).
2 kinds of Nucleotic Acid Vaccine:
RNA (RiboNucleic Acid)
DNA (DeoxyriboNucleic Acid)
f. Virus Vaccines = Whole-virus Vaccines
Vaccines that use a weakened or inactivated version of the coronavirus to provoke immune response. They require extensive testing for safety because they can cause disease.
Weakened coronavirus
Inactive coronavirus
* Inactivated Coronavirus
(In Use)
1. Sinopharm and Beijing Institute of Biological Products.
2. Sinovac Biotech (private Chinese company). Called CoronaVac.
3. Sinopharm (state owned Chinese company) and Wuhan Institute of Biological Products.
4. Bharat Biotech (India), Indian Council of Medical Research and National Institute of Virology.
(In Study)
5. Institute of Medical Biology at the Chinese Academy of Medical Sciences.
6. The Chumakov Center at the Russian Academy of Sciences.
7. The Research Institute for Biological Safety Problems of Kazakhstan.
8. Shenzhen Kangtai Biological Products. .
9. Erciyes University (of Turkey).
* Weakened coronavirus
(In Study)
1. Codagenix (NY-based) develops vaccines based on live-attenuated viruses, but with a twist: they create the viruses from scratch. Researchers rewrite the genome of viruses, introducing hundreds of mutations. Then they manufacture RNA molecules encoding the rewritten genes. In special host cells, the molecules can give rise to full-blown viruses. But thanks to their numerous mutations, they are too weak to cause Covid-19 when they delivered in a vaccine.
g. Viral-vector Vaccines
Vaccines that use a (different) virus to deliver coronavirus genes into cells and provoke an immune response.
A virus such as measles or adenovirus is genetically egineered so that it can produce coronavirus proteins in the body. These viruses are weakened so they can not cause disease.
There are 2 types: those that can still replicate within cells and those that can not because key genes have been disable.
Replicating viral vector such as weakened measles
Non-replicating viral vector such as adenovirus
* Non-replicating viral vector - Adenovirus
(In Use)
1. AstraZeneca (British-Swedish company) and University of Oxford: used Chimpanzee Adenovirus (called ChAdOx1).
2. Gamaleya Research Institute, part of Russian Ministry of Health: used combination of 2 adenovirus (Ad5 and Ad26).
3. CansinoBio (Chinese) and Instite of Biology at the country's Academy of Military Medical Sciences: used Adenovirus (called Ad5).
4. Johnson and Johnson and Beth Israel Deaconess Medical Center (in Boston): used Adenovirus 26 (Ad26).
(In Study)
5. Reithera (Italian biotechnology company) and Lazzaro Spallanzani National Institute of Infectious Disease (in Rome): use an adenovirus that infects gorillas.
6. Vaxart: used Adenovius called Ad5 (same viral vector in CansinoBio's vaccine and Russis's Sputnik V)
7. Immunity Bio (California based company): used Ad5, same as CansinBio, which engineered the Ad5 to carry genes for 2 genes from the Coronavirus: 1 for spike protein as usual plus 1 for Nucleocapsid. The CEO of the company is Patrick Soon Shiong, the owner of the LA Times.
8. University of Hongkong and Xiamen University in partnership with Beijing Wantai Biological Pharmacy: vaccine produce part of the coronavirus spike protein. used Nasal spray (?).
9. German Center for Infection Research: vaccine produce gene for the spike protein, which is produced inside the cells that it invades.
* Replicating viral vector - Measles
(Stopped Study)
1. Merck (American company) at Institute Pasteur: used weakened measles virus.
* Viral vector - Vesicular stomatitis virus
(In Study)
1. The Israel Institute for Biological Research: used vesicular stomatitis viruses, carry the genes for the coronavirus spike protein.
(Stopped Study)
2. Merck partnering with IAVI: used vesicular stomititis viruses. Designed their vaccine as apill. Received 38 mill from US government for the research.
h. Protein-based Vaccines
Vaccines that use a coronavirus protein or a protein fragment to provide an immune response.
Coronavirus proteins (called protein subunits) inject directly into the body.
Fragments of proteins or protein shells (called virus-like particles) that mimic the coronavirus's outer coat can also be used.
* Protein Subunits
(In Use)
1. Bektop (Vector Institute), a Russian biological research center: used small portions of viral proteins, known as peptide. Vaccine name is EpiVacCorona.
(Finished Study)
2. Novavax (Maryland-based, USA): used a viral protein of Coronavirus (spike protein).
(In Study)
3. Anhui Zhifei Longcom and Chinese Academy of Medical Sciences: used a combination of viral protein of Coronavirus (spike protein) and an immune- stimulating adjuvant.
4. Sanofi: used viral protein and adjuvants (supplented by GSK).
5. SpyBiotech, a company that spun off frm the University of Oxford: used mixtures of proteins, some from hepatitis B viruses. (The Serum Institute of India run the trial).
6. Baylor College of Medicine, Texas Children's Hosptal, Biological E (Indian company): used viral proteins (spike protein) with adjuvant (made by Dynavax).
7. Clover Pharmaceuticals: used spike protein from coronavirus and adjuvants from GSK (British drugmaker) and Dynavax (American company).
8. NY based COVAXX. a subsidiary of United Biomedical: used several viral proteins.
9. University of Queensland (Australia): used viral proteins altered to draw stronger immune response and adjuvant made by CSL. Agreement with Australia for future 51 million doses.
10. Vaxine (Australian company): used viral protein and adjuvant.
11. Medigan, Taiwan based vaccine maker: used spike proteins and adjuvant from Dynavax.
* Virus-like Particles
(In Study)
1. Medicago (Canada based company), partly funded by the cigarette maker Philip Morris, used a species of tobacco to make the vaccine. They deliver virus genes into leaves, then the plant cells then create protein shells that mimic viruses. Combination with adjuvants to boost the immune system response. On July. Agreement with government of Canada to supply 76 million doses.
2. Kentucky BioProcessing, an American subsidiary of British American Tobacco: engineers a species of tobacco called Nicotiana benthamiana to make viral proteins
3. Adimmune, Taiwan based vaccine: manufactured and used RBD section of the virus' spike protein.
4. West China Hospital of Sichuan University: manufactured and used RBD region of the spike protein. Researchers encode the RBD region in a gene, which they insert into a virus then infect insect cell with the virus, causing them to make molecule in huge amounts.
5. University of Tubingen (in Germany): used 8 parts of 2 viral proteins plus immune-stimulating adjuvant.
i. Nucleic Acid Vaccines = Genetic Vaccines
Vaccines that use one or more of the coronavirus's own genes to provoke an immune response.
Aim to use genetic instructions (in the form of DNA or RNA) for a coronavirus protein that promt an immune response. The nucleic acid (RNA or DNA) is inserted into human cells which then churns out copies of the virus protein; most of them encode the virus's spike protein.
In short:
inject a genetic instruction (DNA or RNA) into the body, then the body produces from this instruction one of the coronavirus's protein (such as spike protein),
then this protein of corona virus will stimulate immune response from the body (like the protein-based vaccines).
2 kinds of Nucleotic Acid Vaccine:
RNA (RiboNucleic Acid)
DNA (DeoxyriboNucleic Acid)
* RNA (= Ribonucleic Acid, a kind of Nucleic Acid)
(In Use)
1. Pfizer (NY based) Biontech (Germany) and Fosunpharma (Chinese drug maker): used mRNA. Produced both Antibodies and T cell response.
2. Moderna and NIH (National Institute of Health): used mRNA (messenger RNA).
(Alomost Finished Study)
3. CureVac (Germany) collaborrated with Elon Musk's company of Tesla: used mRNA.
(In Study)
4. Arcturus (California) and Duke-NUS Medical School (in Singapore): used mRNA, self replicating.
5. Gennova BioPharceuticals in India and Seattle-base HDT Bio self-amplifying RNA
6. Academy of Military Medical Sciences, Suzhou Abogen Biosciences and Walwax Biotechnology: used mRNA.
7. Chulalongkorn University (Thailand) at Chula Vaccine Research Center: used mRNA.
(Stopped Study)
8. Imperial College London and Morningside Ventures: used self- amplifying RNA.
* DNA (= Deoxyribonucleic Acid, a kind of Nucleic Acid)
(Alomost finished Study)
1. Inovio: On November, FDA gave the permission to move forwrard with their Phase 2 trial. Partial hold due to question about the delivery device which delivered into the skin with electric pulses from hand-held device.
2. Zydus dedicated to life (India).
3. AnGes (Japan), Osaka university and Takara Bio.
(In Study)
4. Genexine (Korea) and GeneOne Life Science (S.Korea)
5. Entos Pharmaceutical (Canada)
6. Symvivo (Canada)
7. OncoSec Immunotherapies (New Jersey based): a loop of DNA that encodes both the spike protein and IL-12, causing the body to make extra IL-12 could potentially enhance the immune system's ability to make antibodies to the spike protein.
k. Vaccine Testing Process
*
- Preclinical Testings:
Scientists test a new vaccine on cells and then give it to animals such as mice or monkeys to see if it produces an immune response. We have confirmed 87 preclinical vaccines in active development.
- Phase 1 Safety Trials:
Scientists give the vaccine to a small number of people to test safety and dosage as well as to confirm that it stimulates the immune system.
- Phase 2 Expended Trials:
Scientists give the vaccine to hundreds of people split into groups, such as children and the elderly, to see if the vaccine acts differently in them. These trials further test the vaccine’s safety and ability to stimulate the immune system.
- Phase 3 Efficacy Trials:
Scientists give the vaccine to thousands of people and wait to see how many become infected, compared with volunteers who received a placebo. These trials can determine if the vaccine protects against the coronavirus. In June, the F.D.A. advised vaccine makers that they would want to see evidence that vaccines protect at least 50 percent of those who received it. In addition, Phase 3 trials are large enough to reveal evidence of relatively rare side effects that might be missed in earlier studies.
- Early or Limited Approval:
China and Russia have approved vaccines without waiting for the results of Phase 3 trials. Experts say the rushed process has serious riks.
- Approval:
Regulators in each country review the trial results and decide whether to approve the vaccine or not. During a pandemic, a vaccine may receive emergency use authorization(EUA) before getting formal approval. Once a vaccine is licensed, researchers continue to monitor people who receive it to make sure it’s safe and effective.
- Combined Phases:
One way to accelerate vaccine development is to combine phases. Some coronavirus vaccines are now in Phase 1/2 trials, for example, in which they are tested for the first time on hundreds of people. (Note that our tracker counts a combined Phase 1/2 trial as both Phase 1 and Phase 2.)
- Paused:
If investigators observe worrying symptoms in volunteers, they can put a trial on pause. After an investigation, the trial may resume or be abandoned.
- When can phase 3 be finalized ?
Phase 3 ends when the trial accumulated more than 150 participants that get sick with Coronavirus (or > 150 "events"). Usually 150-160 events. The total number of participants involved in the trial can be 10,000 or more. Number of the events depends on many factors including the time of trial, the number of participants, the severity of the epidemic (more people get sick)...
l. Antibody Tests
1. Rapid diagnostic test (RDT):
This is typically a qualitative (positive or negative) lateral flow assay that is small, portable, and can be used at point of care (POC).
These tests may use blood samples from a finger prick, saliva samples, or nasal swab fluids.
RDTs are often similar to pregnancy tests, in that the test shows the user colored lines to indicate positive or negative results.
In the context of COVID-19, these tests most frequently test for patient antibodies (IgG and IgM), or viral antigen. In some cases, it can be beneficial to measure baseline (before infection) of IgG and IgM titers.
Time to result = 10-30 minutes
What the Test tells:
The presence or absence (qualitative) of antibodies against the virus present in patient serum.
What the Test can not tell:
The quantifiable amount of antibodies in the patient serum, or if these antibodies are able to protect against future infection.
2. Enzyme-linked immunosorbent assay (ELISA):
This test can be qualitative or quantitative and is generally a lab-based test.
These tests usually use whole blood, plasma, or serum samples from patients. The test relies on a plate that is coated with a viral protein of interest, such as Spike protein.
Patient samples are then incubated with the protein, and if the patient has antibodies to the viral protein they bind together. The bound antibody-protein complex can then be detected with another wash of antibodies that produce a color or fluorescent-based readout.
In the contest of COVID-19, these tests most frequently test for patient antibodies (IgG and IgM).
Time to result = 1-5 hours
What the Test tells:
The presence or absence (quantitative) of antibodies against the virus present in patient serum.
What the Test can not tell:
If the antibodies are able to protect against future infection.
3. Neutralization assay:
This test relies on patient antibodies to prevent viral infection of cells in a lab setting. Neutralization assays can tell researchers if a patient has antibodies that are active and effective against the virus, even if they have already cleared the infection.
These tests require whole blood, serum, or plasma samplesfrom the patient.
Neutralization assays depend on cell culture, a lab-based method of culturing cells that allow SARS-CoV-2 growth (like VeroE6 cells). When virus and cells are grown with decreasing concentrations of patient antibodies, researchers can visualize and quantify how many antibodies in the patient serum are able to block virus replication.
This blocking action can happen through the antibody binding to an important cell entry protein on the virus, for example.
Time to result = 3-5 days
What the Test tells:
The presence of active antibodies in patient serum that are able to inhibit virus growth ex vivo, in a cell culture system. Indicates if the patient is protected against future infection.
What the Test can not tell:
It may miss antibodies to viral proteins that are not involved in replication.
(Note that result turnaround times specify only how long it takes to obtain results after a sample is placed in the analyzer; it does not account for sample transportation, in-lab backlogs in processing samples, or reporting of results, which often make for significant delay).
m. Vaccine Efficacy and Effectiveness
When phase 3 ends, the company will report the Vaccine Efficacy (VE). How can the company calculate it ?
For example there are 2 groups of participants for phase 3: Unvaccinated (Placebo) and Vaccinated.
15,000 participants in Unvacinated group
15,000 participants in Vacinated group
30,000 in total
This is a blind study. Each participant does not know which group he or she belongs to.
If there are total 154 participants get sick with Covid-19: 140 in Unvacinated group and 14 in Vaccinated group.
ARU = Attack Rate of Unvaccinated group = 140 / 15,000
ARV = Attack Rate of Vaccinated group = 14 /15,000
VE = Vaccine Efficacy, result in %
With the formula,
VE = ARU - ARV / ARU x 100 = 90%
Vaccine Efficacy of 90% means: for 100 persons received this vaccine, 90 will be protected against the virus.
The criteria for FDA to approve the vaccine is VE > 50%.
*
- Vaccine immunogenicity
Vaccine immunogenicity is a measure of the immune response to a vaccine and usually involves measuring specific antibodies in the blood. For some, but not all vaccines, a defined threshold of specific antibody levels has been correlated with protection. However, this does not definitively tell us if a person is fully protected against disease. If good immune memory has been established, a large rise in antibody levels occurs following a booster dose of vaccine.
- Vaccine efficacy and effectiveness
Vaccine efficacy and effectiveness are measures that compare the rates of disease between vaccinated and unvaccinated people. Efficacy is measured in controlled clinical trials, whereas effectiveness is measured once the vaccine is approved for use in the general population. From these we can identify the proportion of vaccinated people we would expect to be protected by the vaccine.
- Herd immunity (also called community immunity) is an important mechanism by which the larger community is protected. For some diseases, if enough people are immune then transmission of the disease is reduced or eliminated. This is particularly so for diseases such as rubella and pneumococcal disease. High vaccine coverage must be maintained in order to prevent the disease re-entering the population.
- No vaccine is 100% effective, a small percentage of people are not protected after vaccination and for others the protection may wane over time. Also, some people are unable to be vaccinated due to certain conditions such as immune suppression. Maintaining immunity in those around these people protects them from disease.
n. Immune Response to Infection
* The immune response to viral (and bacterial or parasitic) infection comprises innate and adaptive defenses.
The innate response functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.
The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader.
* Innate Immune Response
Phagocytosis of Cellular Defences of Innate Immunity from Macrophages (from Monocytes), Neutrophils, Basophils, Eosinophils, Phagocytes...
The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.
* Adaptive Immune Response:
Cellular Immunity = Cell-mediated Immunity
Humoral Immunity = Antibody-mediated Immunity
Infection causes Immune response (Adaptive Immunity)
1. Specialized Antigen Presenting Cell (APC cell) engulf the virus and display portions of it to activate T-helper cell.
2. T-helper cells enable other immune response:
B cell makes Antibodies that can block the virus from infecting cells as well as mark the virus for destruction. (Humoral Immunity)
Cytotoxic T cells identify and destroy infected cells. (Cellular Immunity)
The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.
Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
Actually, there are:
Cytotoxic T cell (CD8-positive=CTL) to kill Antigens by Apoptosis and Phagocytosis (from Opsonisation).
Helper T cell (CD4-positive=Th Cell) helps to produce B cell
B cell stimulates to produce Plasma Cell, in turn produces Antibody.
Apoptosis:
Functions of Antibody:
Neutralization
Opsonization for Phagocytosis of by T cell or other cells (Macrophages...).
Complement recruitment
Other Functions of Antibody especially for Viral Infection such as Coronavirus:
* Memory of The Adaptive Immune System
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. (The innate immune response does not need the memory).
Memory response from primary response:
The first adaptive response against a virus – called the primary response – often takes days to mature.
In contrast, a memory response develops within hours of infection (known as secondary response)
Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
Memory cells:
Helper T cell (CD4-positive=Th Cell) and Cytotoxic T cell (CD8-positive=CTL)
B cell
The Memory after the natural infection or the vaccination is the key to protect the human being against the Coronavirus. The future can answer its duration, probably up to a year. The primary adaptive immunity starts several weeks after the infection or vaccination but the secondary response is much faster and larger.
(Immunity after natural infection or vaccination)
o. Monoclonal Antibody
Antibodies made in a laboratory act a lot like natural antibodies to limit the amount of virus in your body. They are called monoclonal antibodies.
This is passive artificial adaptive immunity.
There 2 commercial products of monoclonal antibodies using for treatment of Covid-19 with mild or moderate illnesses (to prevent from progressing to severe or critical illnesses).
Regeneron (cocktail): 2 monoclonal antibodies (Casirivimab and Imdevimab)
Eli Lilly: 2 monoclonal antibodies (Bamlanivimab and Etesevimab)
Regeneron announced that its antibody cocktail is effective against both the U.K. (B.1.1.7) and South African variant (B.1.351).
p. Herd Immunity
The effectiveness of the vaccine and its role in the herd immunity is also under the consideration from many epidemiologists.
All of the vaccines working together will help us achieve herd immunity. We probably need 65% to 85% of the population to have protection against the virus. And that end goal becomes a lot more realistic when we’ve got a mix of highly efficacious vaccines.
The knowledge about Herd Immunity still be limited.
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Sources:
1. Basics of coronavirus and its vaccines (Bs Phan Thượng Hải)
2. Race for Coronavirus: A Graphic Guide (Even Callaway)
3. Coronavirus Vaccine Trackers (NY Times)
4. Coronavirus Vaccine Trackers (CNN)
5. Covid 19 Vaccine Efficacy Summary (IHME)
http://www.healthdata.org/covid/covid-19-vaccine-efficacy-summary
6. Germs: Understand and protect against bateria, viruses and infections (Mayo Clinic)
https://www.mayoclinic.org/diseases-conditions/infectious-diseases/in-depth/germs/art-20045289
7. Related articles and pictures (Google)
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