COVID-19 Summary List of Phase II Potential Vaccines
5/4/20
Justin Avila
justinsavila@gmail.com
If you have been keeping up with the news lately, you know that pharmaceutical companies are scrambling to develop treatments, cures, preventive vaccines and diagnostic kits to conquer COVID-19. According to the WHO, there are currently 83 such projects being researched; and the number is growing rapidly. This makes communicating the ideas and their status difficult, as there are too many different academic articles to review and compare in a reasonably short period of time. The purpose of this article is to summarize the research being done for the treatments in phase II or higher, while also being legible to the average person.
Adenovirus Type 5 Vector (Ad5):
Adenovirus is a family of viruses that is known to infect the respiratory and enteric tracts 1. Although there are 51 different serotypes 2, Adenovirus 5 is one of the most studied and used adenovirus’s 1. Researchers have taken a mild strain of this virus and removed its ability to replicate. They then inserted the genes that encode outer-surface structures from pathogenic viruses into the disabled Adenovirus Type 5 virus. This new genetically modified virus causes a hosts immune system to attack any virus that has the added structures. In the case of the coronavirus that causes COVID-19, the spikes on the surface of the virus have been added to the Ad5 vector 26.
Since Ad5 has been widely researched, there are a lot of studies that can potentially help combat COVID-19, since there are similarities between Ad5 and Coronavirus. One study showed that human IgM (hIgM, a human antibody) was unable to bind to Ad5 as a result of FX 3. FX (coagulating factor X) is a coagulation factor, that is produced in the liver through vitamin K 4. In short, FX’s effect on Ad5 is that it blocks IgM from being pacified 3. Depending on how similar COVID is to Ad5, reducing FX could help the body combat the virus.
Such a vaccine is currently being developed by CanSino Biological Inc. and Beijing Institute of Biotechnology. China is currently in phase II of clinical evaluation where it is performing a randomized, double-blinded, placebo-controlled phase II clinical trial, which started in 2020-04-10 5.
ChAdOx1:
Chimpanzee adenovirus Oxford 1 and 2 (ChAdOx1 and ChAdOx2) are genetically engineered adenovirus’s that can’t reproduce. These virus’s were potential cures for prostate cancer, MERS, malaria, tuberculosis, influenza and chikungunya, as well as boosting CD4+ and CD8+ T cells 6. Researchers at Oxford were able to optimize the virus by changing the promoter on its DNA so that it has the SARS-CoV-2 spike protein 9. Although the virus’s are similar to each other, Oxford is testing ChAdOx1 as a vaccine for SARS-CoV-2.
This potential vaccine is currently being developed by the University of Oxford’s Jenner Institute and Italian pharmaceutical manufacturer Advent Srl 8. The virus is currently in phase I/II of clinical trial, single-blinded, randomized, multi-center study, which started in April 2020 7.
BNT162:
BNT162 are four potential vaccines that utilizes mRNA to suppress COVID-19. The company is utilizing three different types of mRNA’s and four potential vaccine candidates, two nucleoside modified mRNA (modRNA), one uridine containing mRNA (uRNA), and the fourth vaccine candidate utilizes self-amplifying mRNA (saRNA). All four of these vaccines contain mRNA that is incased in a lipid nanoparticle. The mRNA contain spike sequences that help antibodies know how to fight coronavirus. Although all four vaccines have the same function and achieve the same goal, each of the three types have a unique way to send information to help fight COVID-19 10 11.
modRNA: When the mRNA enters the body, it is viewed as invasive and a threat, which results in antibodies attacking the mRNA. Nucleosides are subunits of nucleic acids, which comprise DNA 12. Incorporating modified nucleosides into the mRNA not only suppresses immunogenic reaction against mRNA drugs, but also increases protein production, and helps to avoid production of anti-drug antibodies 13.
uRNA: Contrary to modRNA, uRNA provokes the immune system to help the body produce the proteins necessary to fight off COVID-19. What makes this different from the other drugs, is that it has the chemical uridine 13. Uridine is a chemical that is easily recognized by toll-like receptors (TLRs) in the immune system 14. This combination of the mRNA spikes and uridine increases the production of proteins that are effective against the coronavirus 13.
saRNA: Lastly, saRNA is one of the few potential vaccines that multiplies itself while not being infectious. saRNA is a normal mRNA, but also has the enzyme replicase encoded as well. This enzyme allows the potential vaccine to replicate part of its mRNA. During this process, the mRNA produces an RNA intermediate that is recognized by immune sensors. The RNA intermediate plus the replication of itself makes this mRNA easily recognizable to the immune system, which allows for the system to increase the production of specific proteins 13.
This potential vaccine is currently being developed by BioNTech RNA Pharmaceuticals GmbH. The virus is currently in phase I/II of clinical trial, using different dosing regiments for four Prophylactic SARS-CoV-2 RNA vaccines on healthy adults which started in April 14th 2020 15.
INO-4800:
INO-4800 is a potential vaccine that helps the body produce proteins and antibodies to fight off coronavirus. This information is translated from DNA in plasmids, that trigger the immune systems cells to create antibodies. The DNA is able to enter the cell through CELLECTRA, a device that sends a brief electrical pulse to open small pores in the cell reversibly 16 17 18.
This potential vaccine is currently being developed by INOVIO. The potential vaccine just completed phase I and is about to start phase II/III of clinical trial 19.
Hydroxychloroquine Sulfate
Hydroxychloroquine sulfate is an antimalarial medicine that treats certain types of malaria, lupus erythematosus, and rheumatoid arthritis 20. It works by reducing inflammation in people with autoimmune diseases (this is where the body’s immune system attacks itself by mistake) 21. However, a study done in a France indicates that hydroxychloroquine doesn’t protect the body from Coronavirus, which leading to a patient dying and two being sent to ICU 27.
Hydroxychloroquine sulfate currently has various studies in variouss countries, testing it in phase IV 22 23 24 25.
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2. N.A (N.D) Adenovirus Type 5, BioRad, Retrieved from https://www.bio-rad-antibodies.com/antigen/viral-adenovirus-type-5-antigen-mpp002.html?f=purified
3. M R Duffy, A Doszpoly, G Turner, S A Nicklin and A H Baker (2016 Apr 14) The relevance of coagulation factor X protection of adenoviruses in human sera, NCBI, retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940928/
4. N.A (March 01, 2020/ 21:26) Coagulation factor X human, DrugBank, retrieved from https://www.drugbank.ca/drugs/DB13148
5. Hou Lihua, Zhu Fengcai (2020-03-17) A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector), Chinese Clinical Trial Register, retrieved from http://www.chictr.org.cn/showprojen.aspx?proj=51154
6. N.A (N.D) A clinical stage company utilizing a world leading T cell-inducing platform, Vaccitech, retrieved from https://www.vaccitech.co.uk/technology/
7. Andrew Pollard (April 24, 2020) A Study of a Candidate COVID-19 Vaccine (COV001), Clinical Trials, retrieved from https://clinicaltrials.gov/ct2/show/NCT04324606?term=vaccine&cond=covid-19&draw=2
8. N.A (April 01, 2020/ 22:10) ChAdOx1 nCoV-19, DugBank, retrieved from https://www.drugbank.ca/drugs/DB15656
9. N.A (April 23, 2020) U.K. Starts Oxford Coronavirus Vaccine Trial as Germany Green-Lights BioNTech and Pfizer, Genetic Engineering & Biotechnology News, retrieved from https://www.genengnews.com/news/uk-starts-oxford-coronavirus-vaccine-trial-as-germany-green-lights-clinical-trial-for-biontech-and-pfizer/
10. Robert Carlson (04/29/2020 - 10:59) BNT162 Vaccine Description, Precision Vaccine, retrieved from https://www.precisionvaccinations.com/vaccines/bnt162-sars-cov-2-vaccine
11. N.A (16 March 2020 - 10:21) BioNTech reports rapid progress on COVID-19 vaccine program to address global public health threat, Pipeline Review, retrieved from https://pipelinereview.com/index.php/2020031674027/Vaccines/BioNTech-reports-rapid-progress-on-COVID-19-vaccine-program-to-address-global-public-health-threat.html
12. N.A (N.D) Nucleoside, Encyclopedia Britannica, retrieved from https://www.britannica.com/science/nucleoside
13. N.A (N.D) Why mRNA represents a disruptive new drug class, BionTech, retrieved from https://biontech.de/how-we-translate/mrna-therapeutics
14. Elias A. Said, Nicolas Tremblay, Mohammed S. Al-Balushi, Ali A. Al-Jabri, and Daniel Lamarre (30 Apr 2018) Viruses Seen by Our Cells: The Role of Viral RNA Sensors, Hidawi, retrieved from https://www.hindawi.com/journals/jir/2018/9480497/
15. N.A (2020-04-14) Clinical trials, EU Clinical Trials Register, retrieved from https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001038-36/DE
16. Darrell Etherington (April 6, 2020 - 3:44 pm EDT) A second potential COVID-19 vaccine, backed by Bill and Melinda Gates, is entering human testing, TechCrunch, retrieved from https://techcrunch.com/2020/04/06/a-second-potential-covid-19-vaccine-backed-by-bill-and-melinda-gates-is-entering-human-testing/
17. Robert Carlson (04/30/2020 - 08:25) INO-4800 DNA Coronavirus Vaccine, Precision Vaccination, retrieved from https://www.precisionvaccinations.com/vaccines/ino-4800-dna-coronavirus-vaccine
18. Jeff Richardson, Ben Matone (Apr 06, 2020, 08:30 ET) INOVIO Initiates Phase 1 Clinical Trial Of Its COVID-19 Vaccine and Plans First Dose Today, Cision, retrieved from https://www.prnewswire.com/news-releases/inovio-initiates-phase-1-clinical-trial-of-its-covid-19-vaccine-and-plans-first-dose-today-301035633.html
19. Jeff Richardson, Ben Matone (April 28, 2020) INOVIO Completes Enrollment in the Phase 1 U.S. Trial of INO-4800 for COVID-19 DNA Vaccine; Interim Results Expected in June, Inovio, retrieved from http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Completes-Enrollment-in-the-Phase-1-US-Trial-of-INO-4800-for-COVID-19-DNA-Vaccine-Interim-Results-Expected-in-June/default.aspx
20. N.A (3/28/20) FACT SHEET FOR PATIENTS AND PARENT/CAREGIVERS EMERGENCY USE AUTHORIZATION (EUA) OF HYDROXYCHLOROQUINE SULFATE FOR TREATMENT OF COVID-19 IN CERTAIN HOSPITALIZED PATIENTS, FDA, retrieved from https://www.fda.gov/media/136538/download
21. N.A (03/2018) Plaquenil-Hydroxychloroquine sulfate 200mg Film-coated Tablets, Zentiva, retrieved from https://www.medicines.org.uk/emc/product/1764/pil
22. Ammar Sarwar (May 1, 2020) Post-Exposure Prophylaxis for Asymptomatic SARS-CoV-2 COVID-19 Patients With choloroquinE Compounds (PEACE), Clinical Trials, retrieved from https://clinicaltrials.gov/ct2/show/NCT04346667?cond=%22Coronavirus+Infections%22&phase=3&draw=2&rank=10
23. Hugo Mendieta Zeron (April 24, 2020) Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19, Clinical Trials, retrieved from https://clinicaltrials.gov/ct2/show/NCT04341493?cond=%22Coronavirus+Infections%22&phase=3&draw=2&rank=3
24. Brian Kendal, Trista Johnson (April 6, 2020) Hydroxychloroquine in Patients With Newly Diagnosed COVID-19 Compared to Standard of Care, Clinical Trials, retrieved from https://clinicaltrials.gov/ct2/show/NCT04334967?cond=%22Coronavirus+Infections%22&phase=3&draw=3&rank=14
25. Ammar Sarwar (May 1, 2020) PRophylaxis of Exposed COVID-19 Individuals With Mild Symptoms Using choloroquinE Compounds (PRECISE), Clinical Trials, retrieved from https://clinicaltrials.gov/ct2/show/NCT04351191?cond=%22Coronavirus+Infections%22&phase=3&draw=3&rank=17
26. Robert Carlson (4/28/2020) Ad5-nCoV COVID-19 Vaccine, Precision Vaccinations, retrieved from https://www.precisionvaccinations.com/vaccines/ad5-ncov-covid-19-vaccine
27. J.M.Molina, C.Delaugerre, J.Le Goff, B.Mela-Lima, D.Ponscarme, L.Goldwirt, N.de Castro (30 March 2020) No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection, Science Direct, retrieved from https://www.sciencedirect.com/science/article/pii/S0399077X20300858?via%3Dihub